Compounds for the treatment of multi-drug resistant bacterial infections

ABSTRACT

The present invention relates to compounds that demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, to their use as medicaments and to their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans. In particular this invention relates to compounds useful for the treatment of bacterial infections in warm-blooded animals such as humans, more particularly to the use of these compounds in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a US National Stage under 35 U.S.C. §371 ofInternational Application No. PCT/GB2006/002207 (filed Jun. 16, 2006)which claims priority under 35 U.S.C. §119 (e) to Application No.60/691,340 (filed on Jun. 16, 2005).

BACKGROUND OF THE INVENTION

The international health community continues to express serious concernthat the evolution of antibacterial resistance will result in strainsagainst which currently available antibacterial agents will beineffective. For example, resistant strains of Gram-positive pathogenssuch as methicillin-resistant Staphylococcus aureus (MRSA),methicillin-resistant coagulase-negative staphylococci (MRCNS),penicillin-resistant Streptococcus pneumoniae and multiple resistantEnterococcus faecium are both difficult to treat and difficult toeradicate. Consequently, in order to overcome the threat of widespreadmulti-drug resistant organisms, there is an on-going need to develop newantibiotics, particularly those with either a novel mechanism of actionand/or containing new pharmacophoric groups.

SUMMARY OF THE INVENTION

These and other needs are met by the invention disclosed herein which isdirected to a compound of formula I:L-U₁-M-U₂—R  I

or a pharmaceutically acceptable salt thereof, or N-oxides thereof,wherein:

L is a group of formula L1-L15:

wherein

indicates the point of attachment;

Z₃, Z₆, and Z₇ are C or N provided that when Z₃, Z₆, or Z₇ is N, thenR₂a, R₂c, or R₂d are absent;

R₂a, R₂b, R₂c, R₂d, R_(e)e, and R_(e)f, are each independently H, halo,cyano, carboxy, nitro, carbamoyl, —CO—(C₁-C₆)alkyl, CO₂—(C₁-C₆)alkyl,(C₁-C₆)alkyl, hydroxy, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,(C₁-C₆)alkoxy, NHCO—(C₁-C₆)alkyl, SO₂(C₁-C₆)alkyl, SO₂NH(C₁-C₆)alkyl, orSO₂N((C₁-C₆)alkyl)₂;

R₂g, R₂g′, and R₂g″ are each independently H, (C₁-C₆)alkyl, orhalo(C₁-C₆)alkyl;

U₁ is CRaRb—CRcRd or CRaRb—CRcRd-CReRf, wherein Ra, Rb, Rc, Rd, Re, andRf are each independently hydrogen or (C₁-C₆)alkyl;

M is a group of formula M1-M5:

wherein R2 is H or carboxy, and wherein

indicate points of attachment;

Ry and Ry′ are each independently H, halo, hydroxy, (C₁-C₆)alkyl,(C₁-C₆)alkoxy, CO₂R″, wherein R″ is H, (C₁-C₆)alkyl, orhalo(C₁-C₆)alkyl, or Ry and Ry′ together with the carbon to which theyare attached form C═O; or Ry and Ry′ together form a bridge;

X and Y are each independently CH₂, O, or NR′;

is a bond or is absent;

n is 1, or 2, or 3;

when M is a group of formula M1 or M4, U₂ is NR′—W, wherein W is CH₂,CO, SO₂,

CH₂CH₂, CH₂CH═CH, or CH₂C≡C, wherein each hydrogen may be optionallyreplaced by halo or (C₁-C₆)alkyl;

when M is a group of formula M2, M3, or M5, U₂ is W wherein W is asdefined herein above;

R′ at each occurrence is independently H, (C₁-C₆)alkyl,—(C₁-C₆)alkylcarboxy, —CO—(C₁-C₆)alkyl, —CO₂(C₁-C₆)alkyl,—CO—NH(C₁-C₆)alkyl, —CO—N((C₁-C₆)alkyl)₂, or SO₂(C₁-C₆)alkyl, any ofwhich may be optionally substituted on carbon with halo, hydroxy,(C₁-C₆)alkyl, (C₁-C₆)alkoxy, SO₂(C₁-C₆)alkyl, NH₂, NH(C₁-C₆)alkyl, orN((C₁-C₆)alkyl)₂;

when W is CH₂, CO or SO₂, R is aryl, heteroaryl, heterocyclyl orortho-fused bicyclic heteroaryl, or when W is

CH₂CH₂, CH₂CH═CH, or CH₂C≡C, R is aryl, heteroaryl, heteroaryloxy,heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylamino;wherein any R may be optionally substituted on carbon; and wherein anyring nitrogen in R may be optionally substituted by (C₁-C₆)alkyl; and

any of L, U₁, M, U₂, or R may be optionally substituted on carbon byone, two or three substituents selected from halo, nitro, cyano,hydroxy, oxo, trifluoromethoxy, trifluoromethyl, amino, carboxy,carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl, ethynyl,methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, heteroaryl,heterocyclyl, acetyl, acetoxy, methylamino, ethylamino, dimethylamino,diethylamino, N-methyl-N-ethylamino, or acetylamino;

with the proviso that when L is a group of formula L8 or L15, W is notCO.

What is also provided is a compound of formula I which is a compound offormula II:

or a pharmaceutically acceptable salt thereof, wherein

R₂a, R₂b, R₂c, and R₂d are each independently H, fluoro, chloro, cyano,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, (C₁-C₆)alkoxy;

is a bond or is absent;

Z is CH or N when

is a bond, or Z is O or NH when

is absent;

U₁ is CRaRb—CRcRd or CRaRb—CRcRd-CReRf, wherein Ra, Rb, Rc, Rd, Re andRf are each independently hydrogen or (C₁-C₆)alkyl;

M is a group of formula M1a or M2-M5:

in the trans configuration relative to “*”, wherein R2 is H or carboxy;

Ry and Ry′ are each independently H, hydroxy, fluoro, chloro, methoxy,carboxy, CO₂(C₁-C₆)alkyl, or (C₁-C₆)alkyl, or together with the carbonto which they are attached form C═O; or Ry and Ry′ together form abridge;

X is CH₂, NH, N[CO—(C₁-C₆)alkyl], N[SO₂(C₁-C₆)alkyl], N(C₁-C₆)alkyl, orO;

Y is CH₂, NH, N[CO—(C₁-C₆)alkyl], N[SO₂(C₁-C₆)alkyl], N(C₁-C₆)alkyl, orO;

is a bond or is absent;

n is 1, 2, or 3;

when M is a group of formula M1a or M4, U₂ is NR′—W, wherein R′ is H,(C₁-C₆)alkyl, —(C₁-C₆)alkylcarboxy, —CO—(C₁-C₆)alkyl, —CO₂(C₁-C₆)alkyl,—CO—NH(C₁-C₆)alkyl, —CO—N((C₁-C₆)alkyl)₂, any of which may be optionallysubstituted on carbon with halo, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,SO₂(C₁-C₆)alkyl, NH₂, NH(C₁-C₆)alkyl, or N((C₁-C₆)alkyl)₂;

W is CH₂, CO, SO₂, CH₂CH₂, CH₂CH═CH, or CH₂C≡C, wherein each hydrogenmay be optionally replaced by halo or (C₁-C₆)alkyl;

when M is a group of formula M2, M3, or M5, U₂ is W; and

when W is CH₂, CO or SO₂, R is aryl, heteroaryl, heterocyclyl orortho-fused bicyclic heteroaryl, or when W is CH₂CH₂, CH₂CH═CH, orCH₂C≡C, R is aryl, heteroaryl, heteroaryl(C₁-C₆)alkyloxy,heteroaryl(C₁-C₆)alkylthio, heteroaryl(C₁-C₆)alkylsulfinyl,heteroaryl(C₁-C₆)alkylsulfonyl, heteroaryl(C₁-C₆)alkylamino; wherein anyR may be optionally substituted on carbon; and wherein any ring nitrogenin R may be optionally substituted by (C₁-C₆)alkyl.

What is also provided is a compound of formula I which is a compound offormula III:

or a pharmaceutically acceptable salt thereof, wherein

R₂a, R₂b, R₂c, and R₂d are each independently H, fluoro, chloro, cyano,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, (C₁-C₆)alkoxy;

Z is CH or N when

is a bond, or, when

is absent, Z is O or NH;

Y′ is N or CR₂, wherein R₂ is H, hydroxy, or carboxy;

U₂ is NR′—W, wherein W is CH₂, CO, SO₂, CH₂CH₂, CH₂CH═CH, or CH₂C≡C,wherein each hydrogen may be optionally replaced by halo or(C₁-C₆)alkyl; and

R is

What is also provided is a compound of formula I which is a compound offormula IV:

or a pharmaceutically acceptable salt thereof, wherein

R₂a, R₂b, R₂c, and R₂d are each independently H, fluoro, chloro, cyano,nitro, (C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, (C₁-C₆)alkoxy, NHCO—(C₁-C₆)alkyl,SO₂(C₁-C₆)alkyl, SO₂NH(C₁-C₆)alkyl, or SO₂N((C₁-C₆)alkyl)₂;

Z is CH or N when

is a bond, or, when

is absent, Z is O or NH;

R′ is H or (C₁-C₆)alkyl;

W is CO, SO₂, or CH₂, wherein each hydrogen may be optionally replacedby halo or (C₁-C₆)alkyl; and

R is

What is also provided is a compound of formula I which is a compound offormula V:

or a pharmaceutically acceptable salt thereof, wherein

R₂a, R₂b, R2c, and R₂d are each independently H, fluoro, chloro, cyano,(C₁-C₆)alkanoyl, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, (C₁-C₆)alkoxy, NHCO—(C₁-C₆)alkyl, SO₂(C₁-C₆)alkyl,SO₂NH(C₁-C₆)alkyl, or SO₂N((C₁-C₆)alkyl)₂;

Z is CH or N when

is a bond, or, when

is absent, Z is O or NH; and

R is

What is also provided by the invention is a compound which is:

-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxyquinolin-2(1H)-one;-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxyquinolin-4(1H)-one;-   Methyl    1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methoxy-1H-indole-2-carboxylate;-   6-[({1-[2-(7-Methoxy-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile;-   2-Oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-1,2-dihydroquinoline-7-carbonitrile;-   6-[({1-[2-(7,8-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   6-[({1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   6-[({1-[2-(7-Fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-fluoroquinolin-2(1H)-one;-   6-[({1-[2-(7-Methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   (3S,4R)-1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylic    acid;-   (3S,4R)-1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidine-3-carboxylic    acid;-   Methyl    (3S,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate;-   Methyl    (3S,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidine-3-carboxylate;-   (3R,4R)-1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylic    acid;-   (3R,4R)-1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidine-3-carboxylic    acid;-   Methyl    (3R,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate;-   Methyl    (3R,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidine-3-carboxylate;-   Cis(±)6-[({1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-3-hydroxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one;-   6-[({1-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   6-[({1-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methoxy-2H-1,4-benzothiazin-3(4H-one;-   6-[({1-[2-(6-Fluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-fluoro-2H-1,4-benzoxazin-3(4H)-one;-   6-[({1-[2-(6-Chloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   6-[({1-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3    (4H)-one;-   3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;-   6-{[(1-{2-[3-Oxo-6-(trifluoromethoxy)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   6-[({1-[2-(6-Fluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one;-   4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;-   6-[({1-[2-(6-Bromo-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   6-[({1-[2-(6-Hydroxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   4-{2-[4-({[2-(2,5-Difluorophenyl)cyclopropyl]methyl}amino)piperidin-1-yl]ethyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;-   6-[({1-[2-(6,8-Difluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   4-[2-(4-{[(2E)-3-(2,5-Difluorophenyl)prop-2-en-1-yl]amino}piperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;-   6-[({trans-4-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   3-Oxo-4-[2-(trans-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}cyclohexyl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;-   6-Bromo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2H-pyrido[3,2-b][1,4]oxazin-3    (4H)-one;-   6-[({1-[2-(6-Nitro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbonitrile;-   3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamide;-   Methyl    3-oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate;-   6-[({1-[2-(6-Acetyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   6-Acetyl-4-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-2H-1,4-benzoxazin-3(4H)-one;-   4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methyl-2H-1,4-benzoxazin-3(4H)-one;-   3-Oxo-4-[2-(6-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;-   4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-2H-1,4-benzoxazin-3(4H)-one;-   6-{[(1-{2-[6-(1-Hydroxyethyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   Ethyl    N-{1-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}-N-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]glycinate;-   6-{[(1-{2-[6-(Methylsulfonyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H-one;-   6-{[(1-{2-[6-(Ethylsulfonyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   6-[({1-[2-(7-Methoxy-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   7-Methoxy-3-methyl-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]quinazoline-2,4(1H,3H)-dione;-   4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-oxopiperidin-1-yl}ethyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one;-   6-[({1-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-oxopiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   3-Oxo-4-[2-(2-oxo-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;-   6-({4-[3-(7-Methoxy-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)propyl]piperazin-1-yl}methyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   4-{3-[4-(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)piperazin-1-yl]propyl}-6-methoxy-2H-1,4-benzoxazin-3(4H)-one;-   4-[2-({1-[(2E)-3-(2,5-Difluorophenyl)prop-2-en-1-yl]piperidin-4-yl}amino)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-one;-   4-(3-{4-[(2E)-3-(2,5-Difluorophenyl)prop-2-en-1-yl]piperazin-1-yl}propyl)-6-methoxy-2H-1,4-benzoxazin-3    (4H-one;-   6-[({1-[2-(6-Methoxy-2-oxo-1,7-naphthyridin-1(2H-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   Methyl    1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate;-   4-[3-(6-Cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]-1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-l-yl]piperidine-3-carboxylic    acid;-   7-Fluoro-3-methyl-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]quinazoline-2,4(1H,3H-dione;-   7-Chloro-1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-1,8-naphthyridin-2(1H)-one;-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxy-1,8-naphthyridin-2(1H)-one;-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-fluoroquinoxalin-2(1H)-one;-   6-[({1-[2-(7-Fluoro-2-oxoquinoxalin-1(2H-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-fluoroquinoxalin-2(1H)-one;-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxyquinoxalin-2(1H)-one;-   6-[({1-[2-(7-Methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3    (4H)-one;-   6-[({1-[2-(7-Methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one;-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6,7-difluoroquinoxalin-2(1H)-one;-   6-[({1-[2-(6,7-Difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H-one;-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7,8-difluoroquinoxalin-2(1H)-one;-   6-[({1-[2-(7,8-Difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   6-[({1-[2-(6,7-Dimethoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   6-[({1-[2-(7-Methoxy-3-methyl-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-2(1H)-one;-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-4(1H)-one;-   Cis(±)6-[({1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-3-methoxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   7-Fluoro-2-oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-1,2-dihydroquinoline-5-carbonitrile;-   5-Fluoro-2-oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-1,2-dihydroquinoline-7-carbonitrile;-   7-Fluoro-1-[2-(4-{[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}piperidin-1-yl)ethyl]quinoxalin-2(1H)-one;-   1-[2-(4-{[(2,2-Dimethyl-3,4-dihydro-2H-chromen-6-yl)methyl]amino}piperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one;-   1-[2-(4-{[(1,3-Dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl]amino}piperidin-1-yl)ethyl]-57-difluoroquinolin-2(1H)-one;-   5,7-Difluoro-1-(2-{4-[(5,6,7,8-tetrahydronaphthalen-2-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-2(1H)-one;-   5,7-Difluoro-1-[2-(4-{[(6-fluoro-4H-1,3-benzodioxin-8-yl)methyl]amino}piperidin-1-yl)ethyl]quinolin-2(1H)-one;-   5,7-Difluoro-1-(2-{4-[(1H-indol-6-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-2(1H)-one;-   1-(2-{4-[(2,3-Dihydro-1H-inden-5-ylmethyl)amino]piperidin-1-yl}ethyl)-5,7-difluoroquinolin-2(1H)-one;-   5,7-Difluoro-1-[2-(4-{[(1-methyl-1H-1,2,3-benzotriazol-5-yl)methyl]amino}piperidin-1-yl)ethyl]quinolin-2(1H)-one;-   5,7-Difluoro-1-(2-{4-[(1H-indol-5-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-2(1H)-one;-   5,7-Difluoro-1-[2-(4-{[(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methyl]amino}piperidin-1-yl)ethyl]quinolin-2(1H)-one;-   1-(2-{4-[(2,1,3-Benzoxadiazol-5-ylmethyl)amino]piperidin-1-yl}ethyl)-7-fluoroquinoxalin-2(1H)-one;-   N-{1-[2-(7-Fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}-2,3-dihydro-1,4-benzodioxine-6-sulfonamide;-   N-{1-[2-(7-Fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide;-   5-Fluoro-N-{1-[2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}-1H-indole-2-carboxamide;-   N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}-6-morpholin-4-ylnicotinamide;-   N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}-2,3-dihydro-1,4-benzodioxine-2-carboxamide;-   N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}-1-methyl-1H-1,2,3-benzotriazole-5-carboxamide;-   N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}-3-(2-methyl-1,3-thiazol-4-yl)benzamide;-   N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}-4-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide;-   3-Oxo-4-[2-((2R,5S)-5-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;-   3-Oxo-4-[2-((2S,5R)-5-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;-   6-[({1-[2-(5,7-Difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   6-[({1-[2-(6,8-Difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   2-Oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-1,2-dihydroquinoxaline-6-carbonitrile;-   3-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydroquinoxaline-6-carbonitrile;-   6-[({1-[2-(6-Methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3    (4H)-one;-   4-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one;-   6-[({1-[2-(6-Chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   6-Chloro-4-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-1,2,4-benzotriazin-3    (4H)-one 1-oxide;-   6-[({1-[2-(6-Chloro-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   4-(2-{(2S,5R)-5-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-2-yl}ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;-   6-[({1-[2-(7-Bromo-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3    (4H)-one;-   2-Oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonitrile;-   2-Oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide;-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-methylpiperidin-1-yl}ethyl)-5,7-difluoroquinolin-2(1H)-one;-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile;-   Cis±4(1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylic    acid;-   Methyl    (Cis±4)-1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate;-   Cis±1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-hydroxypiperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile;-   Cis±1-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile;-   5,7-Difluoro-1-(2-{4-[(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-2(1H)-one;-   Cis±1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-methoxypiperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile;-   Cis±1-[2-(3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile;-   Cis±1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoropiperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile;-   Cis±1-[2-(3fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile;-   Cis±1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-hydroxypiperidin-1-yl}ethyl)-7-fluoroquinoxalin-2(1H)-one;-   Cis±6-[({1-[2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]-3-hydroxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   Cis±1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-methoxypiperidin-1-yl}ethyl)-7-fluoroquinoxalin-2(1H)-one;-   Cis±6-[({1-[2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]-3-methoxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   Cis±1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoropiperidin-1-yl}ethyl)-7-fluoroquinoxalin-2(1H)-one;-   Cis±6-[({1-[2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]-3-fluoropiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   Cis±1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-hydroxypiperidin-1-yl}ethyl)-7-methoxyquinoxalin-2(1H)-one;-   Cis±6-[({1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]-3-hydroxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   Cis±1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-methoxypiperidin-1-yl}ethyl)-7-methoxyquinoxalin-2(1H)-one;-   Cis±6-[({1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]-3-methoxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   Cis±1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-3-fluoropiperidin-1-yl}ethyl)-7-methoxyquinoxalin-2(1H)-one;-   Cis±6-[({1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]-3-fluoropiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;-   Cis±4-[2-(3-hydroxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;-   Cis±4-[2-(3-methoxy-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;-   Cis±4-[2-(3-fluoro-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile;-   1-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxy-3,4-dihydroquinoxalin-2(1H)-one;-   5,7-Difluoro-1-[2-(4-{[(1-oxo-1,3-dihydro-2-benzofuran-5-yl)methyl]amino}piperidin-1-yl)ethyl]quinolin-2(1H)-one;-   6-[({1-[2-(7-Methoxy-2-oxoquinoxalin-1(2H)-yl)propyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one;    or-   5,7-Difluoro-1-(2-{4-[(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-2(1H)-one.

The invention also provides a pharmaceutical composition comprising acompound of formulas I-V admixed with a pharmaceutically acceptableadjuvant, carrier, or excipient.

The invention also provides a method of treating a bacterial infectioncomprising administering a therapeutically effective amount of acompound of formulas I-V to a mammal in need thereof.

The invention also provides a method of treating a bacterial infectionin a warm-blooded animal, such as a human being, in need of suchtreatment, which comprises administering to said animal an effectiveamount of a compound of formulas I-V or a pharmaceutically-acceptablesalt thereof.

The invention also provides a method for inhibiting bacterial DNA gyrasein a warm-blooded animal, such as a human being, in need of suchtreatment which comprises administering to said animal an effectiveamount of a compound of formulas I-V or a pharmaceutically acceptablesalt.

The invention also provides a compound of formulas I-V andpharmaceutically acceptable salts thereof for use as a medicament.

The invention also provides the use of a compound of formulas I-V or apharmaceutically acceptable salt thereof in the manufacture of amedicament for use in the production of an anti-bacterial effect in awarm-blooded animal such as a human being.

The invention also provides the use of a compound of formulas I-V or apharmaceutically acceptable salt thereof in the manufacture of amedicament for use in the treatment of a bacterial infection in awarm-blooded animal such as a human being.

The invention also provides a process for making a compound of formulasI-V, comprising one of the following:

-   (a) N-alkylation of L with X—U₁M, wherein X is a leaving group in    the presence of a base to form LU₁M, wherein U₁ is CH₂CH₂, followed    by attachment of U₂ and R via functional group manipulation,    alkylation, or reductive amination;

-   (b) N-alkylation of L with HO—U₁M, under Mitsunobu conditions to    form LU₁M, followed by attachment of U₂ and R via functional group    manipulation, alkylation, or reductive amination;

-   (c) N-alkylation of L with bromo- or chloroacetic acid or a    derivative thereof to form L-CH2CO₂H followed by    -   i) activation of the acid moiety in L-CH2CO₂H;    -   ii) amide coupling to form LU₁M, wherein U₁ is CH₂CO,    -   iii) attachment of U₂ and R via functional group manipulation,        alkylation, or reductive amination; and    -   iv) optional reduction of the carbonyl moiety in U₁ to form a        compound wherein U₁ is CH₂CH₂.

-   (d) N-alkylation of L with X—(CH₂)_(n)CH═CH₂ wherein X is a leaving    group and n is 1 or 2 to form L-(CH₂)_(n)CH═CH₂, followed by:    -   i) oxidative cleavage using an oxidant such as ozone or sodium        periodate (with reductive workup) to form L-(CH₂)_(n)CH₂OH;    -   ii) conversion of the alcohol moiety in L-(CH₂)_(n)CH₂OH to a        leaving group;    -   iii) reaction of L-(CH₂)_(n)CH₂—Y with M, in the presence of a        base to form LU₁M; and    -   iv) attachment of U₂ and R via functional group manipulation,        alkylation, or reductive amination;

-   (e) N-alkylation of L with X—(CH₂)_(n)CH═CH₂ wherein X is a leaving    group and n is 0 or 1 to form L-(CH₂)_(n)CH═CH₂, provided that when    n is 0, a metal catalyst is optionally used, followed by:    -   i) hydroboration followed by an oxidative workup to form to form        L-(CH₂)_(n)CH₂CH₂OH;    -   ii) conversion of the alcohol moiety in L-(CH₂)_(n)CH₂CH₂OH to a        leaving group;    -   iii) reaction of L-(CH₂)_(n)CH₂CH₂-“LG” with M, in the presence        of a base to form LU₁M; and    -   iv) followed by attachment of U₂ and R via functional group        manipulation, alkylation, or reductive amination;

-   (f) Oxidation of the alcohol intermediate

in d) and e) supra to the aldehyde

followed by

-   -   i) reductive amination with MU₂; to form LU₁MU₂, wherein U1 is        CH₂CH₂;    -   ii) reductive amination with R; or

-   (g) N-alkylation of L with X—(CH₂)_(n)CH₂CH₂OH, wherein X is a    leaving group and n is 0 or 1 to form the intermediate    L-(CH₂)_(n)CH₂CH₂OH as depicted in (e), supra, followed by    -   i) conversion of the alcohol moiety in L-(CH₂)_(n)CH₂CH₂OH to a        leaving group;    -   ii) reaction of L-(CH₂)_(n)CH₂CH₂-“LG” with M, in the presence        of a base to form LU₁M; and    -   iii) followed by attachment of U₂ and R via functional group        manipulation, alkylation, or reductive amination.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise stated, the following terms used in the specificationand claims have the following meanings.

DEFINITIONS

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, pentyl, and the like, that may be optionally substituted.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms, containing at least one double bond, e.g., ethenyl(—CH═CH₂), propenyl, and the like that may be optionally substituted.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms, e.g., methylene (—CH₂—), ethylene(—CH₂CH₂—), propylene, 2-methylpropylene, pentylene, and the like thatmay be optionally substituted.

“Acyl” means a radical —C(O)R where R is hydrogen, alkyl, alkenyl,cycloalkyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl orheteroaryl, e.g., acetyl, benzoyl, thienoyl, and the like that may beoptionally substituted.

“Acyloxy” means a radical —OC(O)R where R is hydrogen, alkyl, alkenyl,cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl,e.g., acetoxy, benzoyloxy, and the like that may be optionallysubstituted.

“Halo” means fluoro, chloro, bromo or iodo.

“Haloalkyl” means alkyl substituted with one or more same or differenthalo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃, and the like.

“Cycloalkyl” means a saturated monovalent cyclic hydrocarbon radical ofthree to six ring carbons, e.g., cyclopropyl, cyclohexyl, and the likethat may be optionally substituted.

“Amine” or “amino” refers to radicals of the general formula —NRR′,wherein R and R′ are independently selected from hydrogen or ahydrocarbyl radical, or wherein R and R′ combined form a heterocycle.Examples of amino groups include: —NH₂, methyl amino, diethyl amino,anilino, benzyl amino, piperidinyl, piperazinyl and indolinyl.

“Monosubstituted amino” means a radical —NHR where R is alkyl,heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionallysubstituted phenyl, e.g., methylamino, (1-methylethyl)amino,phenylamino, and the like.

“Disubstituted amino” means a radical —NRR′ where R and R′ areindependently alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl,cycloalkylalkyl or optionally substituted phenyl. Representativeexamples include, but are not limited to, dimethylamino,methylethylamino, di(1-methylethyl)amino, methylbenzylamino, and thelike.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 10 ring atoms, and optionally substituted independentlywith one or more substituents, preferably one, two or three substituentsselected from alkyl, haloalkyl, heteroalkyl, cycloalkyl,cycloalkylalkyl, halo, cyano, nitro, acyloxy, alkoxy, optionallysubstituted phenyl, heteroaryl, heteroaralkyl, amino, monosubstitutedamino, disubstituted amino, acylamino, hydroxyamino, amidino, guanidino,cyanoguanidinyl, hydrazino, hydrazido, —OR [where R is hydrogen, alkyl,haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substitutedphenyl, heteroaryl or heteroaralkyl], —S(O)_(n)R [where n is an integerfrom 0 to 2 and R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl,cycloalkylalkyl, optionally substituted phenyl, heteroaryl,heteroaralkyl, amino, mono or disubstituted amino], —NRSO₂R′ (where R ishydrogen or alkyl and R′ is alkyl, amino, monosubstituted ordisubstituted amino) —C(O)R (where R is hydrogen, alkyl, alkenyl,cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl),—COOR (where R is hydrogen, alkyl, optionally substituted phenyl,heteroaryl or heteroaralkyl), -(alkylene)-COOR (where R is hydrogen,alkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl),methylenedioxy, 1,2-ethylenedioxy, —CONR′R″ or -(alkylene)CONR′R″ (whereR′ and R″ are independently selected from hydrogen, alkyl, cycloalkyl,haloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryland heteroaralkyl). More specifically the term aryl includes, but is notlimited to, phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.

The term “ortho-fused” as used in the phrase “ortho-fused bicyclicsubunit” means a bicyclic saturated, partially aromatic or fullyaromatic, fully unsaturated or partially saturated, carbocyclic orheterocyclic ring system wherein the two rings have only two atoms andone bond in common. Both rings may be aromatic; for example, such as innaphthalene, pteridine, cinnoline, quinazoline, quinoxaline,naphthyridine, phthalazine, quinoline, isoquinoline, quinolizine,purine, indazole, indole, isoindole, indolizine, or pyrrolizine and thelike.

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radicalof 5 to 10 ring atoms containing one, two, or three ring heteroatomsselected from N, O, or S, the remaining ring atoms being C. For theavoidance of doubt, “heteroaryl” includes “ortho-fused bicyclicheteroaryl”. The aromatic radical is optionally substitutedindependently with one or more substituents, preferably one or twosubstituents selected from oxo, alkyl, haloalkyl, heteroalkyl,cycloalkyl, cycloalkylalkyl, halo, cyano, nitro, acyloxy, optionallysubstituted phenyl, amino, monosubstituted amino, disubstituted amino,acylamino, hydroxyamino, amidino, guanidino, cyanoguanidinyl, hydrazino,hydrazido, —OR [where R is hydrogen, alkyl, haloalkyl, alkenyl,cycloalkyl, cycloalkylalkyl or optionally substituted phenyl],—S(O)_(n)R [where n is an integer from 0 to 2 and R is hydrogen, alkyl,haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substitutedphenyl, amino, mono or disubstituted amino], —C(O)R (where R ishydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl oroptionally substituted phenyl), —COOR (where R is hydrogen, alkyl, oroptionally substituted phenyl), -(alkylene)-COOR (where R is hydrogen,alkyl or optionally substituted phenyl), methylenedioxy,1,2-ethylenedioxy, —CONR′R″ or -(alkylene)-CONR′R″ (where R′ and R″ areindependently selected from hydrogen, alkyl, cycloalkyl, haloalkyl,cycloalkylalkyl or optionally substituted phenyl). The term heteroarylincludes, but is not limited to pyridyl, pyrrolyl, thiophene, pyrazolyl,thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, indolyl, carbazolyl,azaindolyl, benzopyranyl, benzotriazolyl, benzisoxazolyl, purinyl,quinolinyl, benzopyranyl, and derivatives thereof.

“Heterocycle” or “Heterocyclyl” means a saturated, partially unsaturatedor fully unsaturated cyclic radical of 3 to 8 ring atoms in which one ortwo ring atoms are heteroatoms selected from N, O, or S(O)_(n) (where nis an integer from 0 to 2). The heterocyclo ring may be optionallysubstituted independently with one, two or three substituents selectedfrom alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, halo, cyano, acyl, acylamino, amino,monosubstituted amino, disubstituted amino, —COOR (where R is hydrogenor alkyl), —XR (where X is O or S(O), where n is an integer from 0 to 2and R is hydrogen, alkyl, haloalkyl, cycloalkyl, aralkyl, aryl,heteroaryl or heteroaralkyl) or —CONR′R″ (where R′ and R″ areindependently selected from hydrogen or alkyl). Representative examplesinclude, but are not limited to tetrahydropyranyl, piperidino,1-(4-chlorophenyl)piperidino, and the like.

In one aspect of the invention “Ry and Ry′ together form a bridge”. Abridge is a bond, a carbon atom or two carbon atoms connecting twodifferent ring atoms of M which are meta or para to each other.Particularly the bridge is a bond. Particularly the bridge is one carbonatom. Alternatively the bridge is two carbon atoms. Examples of M where“Ry and Ry′ together form a bridge” are:

(M1, bridge is a bond, atoms of M are meta to each other),

(M2, bridge is one carbon atom, atoms of M are meta to each other),

(M4, bridge is two carbon atoms, atoms of M are para to each other), and

(M5, bridge is a bond, atoms of M are meta to each other).

“Aralkyl” means a radical —R_(a)—R_(b) where R_(a) is bound to R_(b) andR_(a) is an alkylene group and R_(b) is an aryl group as defined abovee.g., benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and thelike.

“Heteroaralkyl” means a radical —R_(a)—R_(b) where R_(a) is bound toR_(b) and R_(a) is an alkylene group and R_(b) is a heteroaryl group asdefined above e.g., pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, andthe like.

“Alkoxy”, “aryloxy” or “heteroaryloxy” means a radical —OR where R is analkyl, aryl or heteroaryl, respectively as defined above e.g., methoxy,phenoxy, pyridin-2-yloxy and the like.

“Alkylthio” and “heteroarylthio” respectively mean an alkyl group orheteroaryl group attached via a thioether linkage.

“Alkylsulfinyl” and “heteroarylsulfinyl” respectively mean an alkylgroup or heteroaryl group attached via a sulfinyl linkage.

“Alkylcarbonyloxy” refers to an alkyl group attached to a CO₂ group, asin alkyl-CO₂—, alkenyl-CO₂—, aryl-CO₂—, respectively, where alkyl is asdefined herein. For example, alkylcarbonyloxy includes but is notlimited to, acetoxy, ethylcarbonyloxy, n- or iso-propylcarbonyloxy, n-,iso-, sec- or tert-butylcarbonyloxy, n-pentylcarbonyloxy,n-hexylcarbonyloxy.

“Optionally substituted” means that the group at issue is optionallysubstituted independently with one, two or three substituents selectedfrom halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl,amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, ethenyl,ethynyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino,dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, or asotherwise provided.

“Amino-protecting group” refers to those organic groups intended toprotect nitrogen atoms against undesirable reactions during syntheticprocedures e.g., benzyl, benzyloxycarbonyl (CBZ), t-butoxycarbonyl(BOC), trifluoroacetyl, and the like.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarized light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. For example, if the Y and Y′substituents in a compound of formula I are attached to the same carbonare different, then the carbon to which they are attached is anasymmetric center and the compound of formula I can exist as an (R)- or(S)-stereoisomer relative to that carbon. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see discussion in Chapter 4 of “Advanced OrganicChemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001).

A “pharmaceutically acceptable excipient” means an excipient that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable, andincludes an excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

A “pharmaceutically acceptable counterion” means an ion having a chargeopposite to that of the substance with which it is associated and thatis pharmaceutically acceptable. Representative examples include, but arenot limited to, chloride, bromide, iodide, methanesulfonate,p-tolylsulfonate, trifluoroacetate, acetate, and the like.

A “pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

-   -   1) acid addition salts, formed with inorganic acids such as        hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,        phosphoric acid, and the like; or formed with organic acids such        as acetic acid, propionic acid, hexanoic acid,        cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic        acid, malonic acid, succinic acid, malic acid, maleic acid,        fumaric acid, tartaric acid, citric acid, benzoic acid,        3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,        methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic        acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,        4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid,        4-toluenesulfonic acid, camphorsulfonic acid,        4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic        acid, 4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid),        3-phenylpropionic acid, trimethylacetic acid, tertiary        butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic        acid, hydroxynapthoic acid, salicylic acid, stearic acid,        muconic acid, and the like; or    -   2) salts formed when an acidic proton present in the parent        compound either is replaced by a metal ion, e.g., an alkali        metal ion, an alkaline earth ion, or an aluminum ion; or        coordinates with an organic base such as ethanolamine,        diethanolamine, triethanolamine, tromethamine,        N-methylglucamine, and the like.    -   3) “Leaving group” has the meaning conventionally associated        with it in synthetic organic chemistry i.e., an atom or group        capable of being displaced by a nucleophile and includes        halogen(such as chloro, bromo, iodo), alkanesulfonyloxy (such as        mesyloxy or trifluorosulfonyloxy) or arenesulfonyloxy (such as        tosyloxy), ester, or amino, and the like.

“Pro-drugs” means any compound which releases an active parent drugaccording to formula I in vivo when such prodrug is administered to amammalian subject. Prodrugs of a compound of formula I are prepared bymodifying functional groups present in the compound of formula I in sucha way that the modifications may be cleaved in vivo to release theparent compound. Prodrugs include compounds of formula I wherein ahydroxy, thio or amino group in compound I is bonded to any group thatmay be cleaved in vivo to regenerate the free hydroxy, amino, or thiogroup, respectively. Examples of prodrugs include, but are not limitedto esters (e.g., acetate, formate, and benzoate derivatives), carbamates(e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups incompounds of formula I, and the like.

“Treating” or “treatment” of a disease includes:

-   -   1) preventing the disease, i.e. causing the clinical symptoms of        the disease not to develop in a mammal that may be exposed to or        predisposed to the disease but does not yet experience or        display symptoms of the disease;    -   2) inhibiting the disease, i.e., arresting or reducing the        development of the disease or its clinical symptoms; or    -   3) relieving the disease, i.e., causing regression of the        disease or its clinical symptoms.

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

Invention Compounds

Referring again to a compound of the invention, the following specificvalues are disclosed.

In a compound of formula I, a specific value for L is

wherein

indicates the point of attachment and Z is CH or N. Other specificvalues for L include the following structures, wherein

has the same meaning.

A specific value for R₂b is H. Other specific values for R₂b includehalo, (C₁-C₆)alkanoyl, cyano, carboxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, hydroxy, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,(C₁-C₆)alkoxy, NHCO—(C₁-C₆)alkyl, SO₂ (C₁-C₆)alkyl, SO₂NH(C₁-C₆)alkyl,or SO₂N((C₁-C₆)alkyl)₂.

To that end, specific values for R₂b include H, methoxy, cyano, fluoro,chloro, trifluoromethoxy, bromo, hydroxy, CONH₂, CO₂Me, MeCO, methyl,1-hydroxyethyl, 2-hydroxyethyl, SO₂Me, and SO₂Et.

A specific value for R₂a, is H. Other specific values for R₂a includehalo, (C₁-C₆)alkanoyl, cyano, carboxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, hydroxy, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,(C₁-C₆)alkoxy, NHCO—(C₁-C₆)alkyl, SO₂(C₁-C₆)alkyl, SO₂NH(C₁-C₆)alkyl, orSO₂N((C₁-C₆)alkyl)₂.

To that end, specific values for R₂a include H, methoxy, cyano, fluoro,chloro, trifluoromethoxy, bromo, hydroxy, CONH₂, CO₂Me, MeCO, methyl,1-hydroxyethyl, 2-hydroxyethyl, SO₂Me, and SO₂Et.

A specific value for R₂c is H. Other specific values for R₂c includehalo, (C₁-C₆)alkanoyl, cyano, carboxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, hydroxy, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,(C₁-C₆)alkoxy, NHCO—(C₁-C₆)alkyl, SO₂(C₁-C₆)alkyl, SO₂NH(C₁-C₆)alkyl, orSO₂N((C₁-C₆)alkyl)₂.

To that end, specific values for R₂c include H, methoxy, cyano, fluoro,chloro, trifluoromethoxy, bromo, hydroxy, CONH₂, CO₂Me, MeCO, methyl,1-hydroxyethyl, 2-hydroxyethyl, SO₂Me, and SO₂Et.

A specific value for R₂d is H. Other specific values for R₂d includehalo, (C₁-C₆)alkanoyl, cyano, carboxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, hydroxy, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,(C₁-C₆)alkoxy, NHCO—(C₁-C₆)alkyl, SO₂(C₁-C₆)alkyl, SO₂NH(C₁-C₆)alkyl, orSO₂N((C₁-C₆)alkyl)₂.

To that end, specific values for R₂d include H, methoxy, cyano, fluoro,chloro, trifluoromethoxy, bromo, hydroxy, CONH₂, CO₂Me, MeCO, methyl,1-hydroxyethyl, 2-hydroxyethyl, SO₂Me, and SO₂Et.

A specific value for R₂e is H. Other specific values for R₂e includehalo, (C₁-C₆)alkanoyl, cyano, carboxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, hydroxy, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,(C₁-C₆)alkoxy, NHCO—(C₁-C₆)alkyl, SO₂(C₁-C₆)alkyl, SO₂NH(C₁-C₆)alkyl, orSO₂N((C₁-C₆)alkyl)₂.

To that end, specific values for R₂e include H, methoxy, cyano, fluoro,chloro, trifluoromethoxy, bromo, hydroxy, CONH₂, CO₂Me, MeCO, methyl,1-hydroxyethyl, 2-hydroxyethyl, SO₂Me, and SO₂Et.

A specific value for R₂f is H. Other specific values for R₂f includehalo, (C₁-C₆)alkanoyl, cyano, carboxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkyl, hydroxy, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy,(C₁-C₆)alkoxy, NHCO—(C₁-C₆)alkyl, SO₂(C₁-C₆)alkyl, SO₂NH(C₁-C₆)alkyl, orSO₂N((C₁-C₆)alkyl)₂.

To that end, specific values for R_(e)f include H, methoxy, cyano,fluoro, chloro, trifluoromethoxy, bromo, hydroxy, CONH₂, CO₂Me, MeCO,methyl, 1-hydroxyethyl, 2-hydroxyethyl, SO₂Me, and SO₂Et.

A specific value for R₂g and R_(e)g′ is H. Other specific values for R₂gand R₂g′ include (C₁-C₆)alkyl, and halo(C₁-C₆)alkyl.

A specific value for U₁ is CH₂CH₂. Other specific values for U₁ includeCH₂CH₂CH₂ and CH₂CH(Me). A further specific value for U₁ is CH(Me)CH₂.

A specific value for M is

wherein Y is O, NH or CH₂ and

is absent or is a bond. Other specific values for M include a group offormula M5 which is

a group of formula M4 which is

or a group of formula M2 which is

wherein

indicates the point of attachment and [U₁] and R2 is H or carboxy, n is1, 2, or 3, and Ry is H, F, hydroxy, (C₁-C₆)alkoxy, or carboxy.

A specific value for M is a group of formula M4 which is

Other specific values for M include groups of formula M4 which are

wherein

indicates the point of attachment.

When M is a group of formula M1 or M4, a specific value for [M]-U₂ is[M]-NHCH₂. When M is a group of formula M1 or M4, other specific valuesfor [M]-U₂ include [M]-NHCH₂CH═CH, [M]-NHSO₂,

when M is a group of formula M2, M3, or M5, a specific value for [M]-U₂is [M]-CH₂CH═CH— or [M]-CH₂CH₂—.

-   -   A specific value for R is 2,1,3-benzothiadiazol-5-yl;        3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl;        2,3-dihydro-benzo[1,4]dioxin-6-yl; 1,2,3-benzothiadiazol-5-yl;        3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl;        7-fluoro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl;        2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl;        2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl;        3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl;        [1,2,3]thiadiazolo[5,4-b]pyridin-6-yl;        3-oxo-3,4-dihydro-2H-pyrido[3,2-b][14]thiazin-6-yl;        7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl;        7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl;        2-thienylthio; or 2,5-difluorophenyl.

More specifically R is

wherein

indicates the point of attachment.

A specific group of compounds of the invention are compounds wherein Lis

wherein

indicates the point of attachment;

is a bond or is absent;

Z is CH or N when

is a bond, or, when

is absent, Z is O or NH;

R₂a, R₂b, R₂c, and R₂d are each independently H, halo, cyano,(C₁-C₆)alkanoyl, carboxy, (C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl,halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, (C₁-C₆)alkoxy, NHCO—(C₁-C₆)alkyl,SO₂(C₁-C₆)alkyl, SO₂NH(C₁-C₆)alkyl, or SO₂N(C₁-C₆)alkyl)₂.

A specific group of compounds of the invention are compounds whereinU₁-M-U₂ is

Y is O, NH, N(C₁-C₆)alkyl, N(CO—(C₁-C₆)alkyl, N[CO—(C₁-C₆)alkyl],N[SO₂(C₁-C₆)alkyl] or CH₂ and

is absent or is a bond. Other specific groups of compounds of theinvention are compounds wherein U₁-M-U₂ is

wherein

“[L]

indicates the point of attachment to L and

indicates the point of attachment to R, and wherein R2 is H or carboxyand n is 1, 2, or 3;

Ra, Rb, Rc, Rd, Re, and Rf are each independently H or (C₁-C₆)alkyl;

Ry is H, F, hydroxy, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, or carboxy;

R′ is H, (C₁-C₆)alkyl, or —(C₁-C₆)alkylcarboxy; and

W is CH₂, CO, SO₂, CH₂CH₂, CH₂CH═CH, or CH₂C≡C, wherein each hydrogenmay be optionally replaced by halo or (C₁-C₆)alkyl;

X is CH₂, NH, N(C₁-C₆)alkyl, N[CO—(C₁-C₆)alkyl], N[SO₂(C₁-C₆)alkyl] orO.

A specific group of compounds of the invention are compounds of formulaI which are compounds of formula II:

or a pharmaceutically acceptable salt thereof, wherein

R₂a, R₂b, R₂c, and R₂d are each independently H, fluoro, chloro, cyano,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, (C₁-C₆)alkoxy;

is a bond or is absent;

Z is CH or N when

is a bond, or Z is O or NH when

is absent;

U₁ is CRaRb—CRcRd or CRaRb—CRcRd-CReRf, wherein Ra, Rb, Rc, Rd, Re andRf are each independently hydrogen or (C₁-C₆)alkyl;

M is a group of formula M1a or M2-M5:

in the trans configuration relative to “*”, wherein R2 is H or carboxy;

Ry and Ry′ are each independently H, halo, (C₁-C₆)alkyl, or togetherwith the carbon to which they are attached form C═O; or Ry and Ry′together form a bridge;

X is CH₂, or provided n is 2 or 3, X is NH, N(C₁-C₆)alkyl, or O;

Y is CH₂, NH, N(C₁-C₆)alkyl, or O;

is a bond or is absent;

n is 1, 2, or 3;

when M is a group of formula M1a or M4, U2 is NR′—W, wherein R′ is H,(C₁-C₆)alkyl,

and W is CH₂, CO, SO₂,

CH₂CH₂, CH₂CH═CH, or CH₂C≡C, wherein each hydrogen may be optionallyreplaced by halo or (C₁-C₆)alkyl, provided that when M is a group offormula M2, M3, or M5, U₂ is W; and

-   -   when W is CH₂, CO or SO₂, R is aryl, heteroaryl, heterocyclyl or        ortho-fused bicyclic heteroaryl, or when W is

CH₂CH₂, CH₂CH═CH, or CH₂C≡C, R is aryl, heteroaryl,heteroaryl(C₁-C₆)alkyloxy, heteroaryl(C₁-C₆)alkylthio,heteroaryl(C₁-C₆)alkylsulfinyl, heteroaryl(C₁-C₆)alkylsulfonyl,heteroaryl(C₁-C₆)alkylamino wherein any R may be optionally substitutedon carbon; and wherein any ring nitrogen in R may be optionallysubstituted by (C₁-C₆)alkyl.

A specific group of compounds of the invention are compounds of formulaI which are compounds of formula III:

or a pharmaceutically acceptable salt thereof, wherein

R₂a, R₂b, R₂c, and R₂d are each independently H, fluoro, chloro, cyano,(C₁-C₆)alkyl, halo(C₁-C₆)alkyl, halo(C₁-C₆)alkoxy, (C₁-C₆)alkoxy;

Z is CH or N when

is a bond, or, when

is absent, Z is O or NH;

Y′ is N or CR₂, wherein R2 is H or carboxy;

Ry is H, fluoro, hydroxy, methoxy, carbomethoxy, or carboxy;

U₂ is NR′—W, wherein R′ is H, (C₁-C₆)alkyl,

or, and W is CH₂, CO, SO₂, CH₂CH₂, CH₂CH═CH, or CH₂C≡C, wherein eachhydrogen may be optionally replaced by halo or (C₁-C₆)alkyl; and

R is 2,1,3-benzothiadiazol-5-yl;3-oxo-3,4-dihydro-2H-1,4-benzothiazin-6-yl;2,3-dihydro-benzo[1,4]dioxin-6-yl; 1,2,3-benzothiadiazol-5-yl;3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl;7-fluoro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl;2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-7-yl;2,3-dihydro-[1,4]dioxino[2,3-c]pyridin-7-yl;3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl;[1,2,3]thiadiazolo[5,4-b]pyridin-6-yl;3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl;7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl;7-fluoro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl;2-thienylthio; or 2,5-difluorophenyl.

A specific group of compounds of the invention are compounds of formulaI which are compounds of formula IV:

or a pharmaceutically acceptable salt thereof, wherein

R₂b is H, halo, cyano, nitro, (C₁-C₆)alkanoyl, carboxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, hydroxy, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, (C₁-C₆)alkoxy, NHCO—(C₁-C₆)alkyl, SO₂(C₁-C₆)alkyl,SO₂NH(C₁-C₆)alkyl, or SO₂N((C₁-C₆)alkyl)₂;

Z is CH or N when

is a bond, or, when

is absent, Z is O or NH;

Ry is H, fluoro, hydroxy, methoxy, carbomethoxy, or carboxy;

R′ is H or (C₁-C₆)alkyl;

W is CO, SO₂, or CH₂, wherein each hydrogen may be optionally replacedby halo or (C₁-C₆)alkyl; and

R is

A specific group of compounds of the invention are compounds of formulaV:

or a pharmaceutically acceptable salt thereof, wherein

R₂b is H, halo, cyano, nitro, (C₁-C₆)alkanoyl, carboxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkyl, hydroxy, halo(C₁-C₆)alkyl,halo(C₁-C₆)alkoxy, (C₁-C₆)alkoxy, NHCO—(C₁-C₆)alkyl, SO₂(C₁-C₆)alkyl,SO₂NH(C₁-C₆)alkyl, or SO₂N((C₁-C₆)alkyl)₂;

Z is CH or N when

is a bond, or, when

is absent, Z is O or NH;

Ry is H, fluoro, hydroxy, methoxy, carbomethoxy, or carboxy;

R′ is H or (C₁-C₆)alkyl; and

R is

A specific group of compounds of the invention are compounds wherein Lis a group of formula L1.

A specific group of compounds of the invention are compounds wherein Lis a group of formula L2.

A specific group of compounds of the invention are compounds wherein Lis a group of formula L3.

A specific group of compounds of the invention are compounds wherein Lis a group of formula L4.

A specific group of compounds of the invention are compounds wherein Lis a group of formula L5.

A specific group of compounds of the invention are compounds wherein Lis a group of formula L6.

A specific group of compounds of the invention are compounds wherein Lis a group of formula L7.

A specific group of compounds of the invention are compounds wherein Lis a group of formula L8.

A specific group of compounds of the invention are compounds wherein Lis a group of formula L9.

A specific group of compounds of the invention are compounds wherein Lis a group of formula L10.

A specific group of compounds of the invention are compounds wherein Lis a group of formula L11.

A specific group of compounds of the invention are compounds wherein Lis a group of formula L12.

A specific group of compounds of the invention are compounds wherein Lis a group of formula L13.

A specific group of compounds of the invention are compounds wherein Lis a group of formula L14.

A specific group of compounds of the invention are compounds wherein Lis a group of formula L15.

A specific group of compounds of the invention are compounds wherein Mis a group of formula M1.

A specific group of compounds of the invention are compounds wherein Mis a group of formula M1a.

A specific group of compounds of the invention are compounds wherein Mis a group of formula M2.

A specific group of compounds of the invention are compounds wherein Mis a group of formula M3.

A specific group of compounds of the invention are compounds wherein Mis a group of formula M4.

A specific group of compounds of the invention are compounds wherein Mis a group of formula M5.

A specific group of compounds of the invention are compounds whereinwhen M is a group of formula M1 or M2, W is CH₂, CO or SO₂.

Preparation of Invention Compounds

In a further aspect, the present invention provides a process forpreparing a compound of the invention or a pharmaceutically-acceptablesalt or an in-vivo hydrolysable ester thereof. It will be appreciatedthat during certain of the following processes, certain substituents mayrequire protection to prevent their undesired reaction. The skilledchemist will appreciate when such protection is required, and how suchprotecting groups may be put in place and later removed.

Examples of protecting groups are disclosed in, for example, ‘ProtectiveGroups in Organic Synthesis’ by Theodora Green (John Wiley & Sons,1999). Protecting groups may be removed by any convenient methoddescribed in the literature or known to the skilled chemist asappropriate for the removal of the protecting group in question, suchmethods being chosen so as to effect removal of the protecting groupwith minimum disturbance of groups elsewhere in the molecule.

Thus, if reactants include, for example, groups such as amino, carboxyor hydroxy it may be desirable to protect the group in some of thereactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylinethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group.

Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonylgroup or an aroyl group may be removed for example, by hydrolysis with asuitable base such as an alkali metal hydroxide, for example lithium orsodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonylgroup may be removed, for example, by treatment with a suitable acid ashydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group that may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon. Resins may also be used as a protecting group.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

A compound of the invention, or a pharmaceutically-acceptable salt or anin vivo hydrolysable ester thereof, may be prepared by any process knownto be applicable to the preparation of chemically-related compounds.Such processes, when used to prepare a compound of the invention, or apharmaceutically-acceptable salt or an in vivo hydrolysable esterthereof, are provided as a further feature of the invention and areillustrated by the following representative examples. Necessary startingmaterials may be obtained by standard procedures of organic chemistry(see, for example, Advanced Organic Chemistry (Wiley-Interscience,2001), Jerry March or Houben-Weyl, Methoden der Organischen Chemie). Thepreparation of such starting materials is described within theaccompanying non-limiting Examples. Alternatively, necessary startingmaterials are obtainable by analogous procedures to those illustratedthat are within the ordinary skill of an organic chemist. Information onthe preparation of necessary starting materials or related compounds(which may be adapted to form necessary starting materials) may also befound in the certain Patent Application Publications, the contents ofthe relevant process sections of which are incorporated herein byreference; for example WO2004/058144; US2004/0224946; WO2004/002992.

The skilled organic chemist will be able to use and adapt theinformation contained and referenced within the above references, andaccompanying Examples therein and also the Examples herein, to obtainnecessary starting materials, and products.

Thus, the present invention also provides that the compounds of theinvention and pharmaceutically-acceptable salts and in vivo hydrolysableesters thereof, can be prepared by a process (a) to (h); and thereafterif necessary:

i) removing any protecting groups;

ii) forming a pro-drug (for example an in-vivo hydrolysable ester);and/or

iii) forming a pharmaceutically-acceptable salt;

wherein said processes (a) to (h) are as follows (wherein the variablesare as defined above unless otherwise stated):

Thus, the present invention also provides that the compounds of theinvention and pharmaceutically-acceptable salts and in vivo hydrolysableesters thereof, can be prepared by a process (a) to (h); and thereafterif necessary:

i) removing any protecting groups;

ii) forming a pro-drug (for example an in-vivo hydrolysable ester);and/or

iii) forming a pharmaceutically-acceptable salt;

wherein said processes (a) to (g) are as follows (wherein the variablesare as defined above unless otherwise stated):

a) By modifying a substituent in, or introducing a substituent intoanother compound of the invention by using standard chemistry (see forexample, Comprehensive Organic Functional Group Transformations(Pergamon), Katritzky, Meth-Cohn & Rees). For example:

-   -   a hydroxy group may be converted into a fluoro group, an acyloxy        group (for instance an acetoxy group), an amino group, a        heterocyclyl group linked through nitrogen (optionally        substituted on a carbon other than a carbon atom adjacent to the        linking nitrogen ring atom—for instance an optionally        substituted amino group). The skilled artisan understands that        such reactions of the hydroxy group take place directly (for        instance by acylation or Mitsunobu reaction) or through the        intermediacy of one or more derivatives (for instance a mesylate        or an azide);    -   an acyloxy group may be converted into a hydroxy group or into        the groups that may be obtained from a hydroxy group (either        directly or through the intermediacy of a hydroxy group); an        alkyl halide group may be converted to a hydroxy group, an amino        group, a thioalkyl group or a heterocyclyl group linked through        nitrogen; a keto group may be reduced to a hydroxy group or an        saturated alkyl group.

b) as depicted in Scheme 1, by alkylation of a suitable bicyclic ringsystem containing a NH group in the ring with a suitable alkylatingreagent containing a leaving group (such as an 0-mesylate, chloro, bromoor iodo) in the presence of a base. Alkylation may be followed byfunctional group manipulations and/or further alkylations or reductiveaminations.

c) As depicted in Scheme 2, by reaction of a suitable bicyclic ringsystem containing a NH group in the ring with a suitable alcohol underMitsunobu conditions, followed by deprotection and reductive aminationwith an aldehyde. This sequence may be followed by functional groupmanipulations and/or further alkylation or reductive aminations.

d) As depicted in Scheme 3, by alkylation of a suitable bicyclic ringsystem containing a NH group in the ring with bromo- or chloroaceticacid or with a derivative thereof, followed by activation of the acidand amide coupling. The amide coupling reaction may be followed byfunctional group manipulations and/or further alkylations or reductiveaminations and optional reduction of the amide moiety.

e) As depicted in Scheme 4, by alkylation of a suitable bicyclic ringsystem containing a NH group in the ring with allylbromide, followed byoxidative cleavage of the double bond with a suitable oxidizing agent,such as ozone or periodate and subsequent manipulation of the resultingalcohol, e.g., by conversion to a mesylate, followed by alkylation. Thealkylation reaction may be followed by functional group manipulationsand/or further alkylation or reductive aminations.

f) As depicted in Scheme 5, by alkylation of a suitable bicyclic ringsystem containing a NH group in the ring with allylbromide, followedhydroboration and subsequent manipulation of the resulting alcohol, e.g.by conversion to a mesylate, followed by alkylation. The alkylationreaction may be followed by functional group manipulations and/orfurther alkylations or reductive aminations.

g) Alternatively, as depicted in Scheme 6, the alcohol intermediate inScheme 5 may be oxidized to the aldehyde, followed by reductiveamination to arrive at the same intermediate.

h) using essentially the procedure described under c), by reaction of asuitable bicyclic ring system containing a NH group in the ring with analcohol

under Mitsunobu conditions; or by alkylation of a suitable bicyclic ringsystem containing a NH group with a derivative of (II), where thealcohol moiety is converted to a leaving group, such as 0-mesylate,followed by deprotection and reductive amination with an aldehyde. Thissequence may be followed by functional group manipulations and/orfurther alkylations or reductive aminations, also using essentially theprocedure described under c).

For example, as depicted in Scheme 7, an O-mesylate alkylating reagentmay be prepared from the alcohol, by reaction with mesyl chloride, inthe presence of a base, such as a trialkyl amine or an immobilizedversion thereof on a resin. It is understood, that such an alkylatingreagent is potentially unstable and needs to be prepared fresh undercareful, controlled conditions.

With respect to (a)-(g) and Schemes 1-5 above, the removal of anyprotecting groups, formation of pharmaceutically-acceptable salts and/orformation of in-vivo hydrolysable esters or amides are within the skillof an ordinary organic chemist using standard techniques. Furthermore,details regarding these transformations; for example, the preparation ofin-vivo hydrolysable ester prodrugs has been described in the sectionabove on such esters.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the above proceduresusing an optically active starting material (formed, for example, byasymmetric induction of a suitable reaction step), or by resolution of aracemic form of the compound or intermediate using a standard procedure,or by chromatographic separation of diastereoisomers (when produced).Enzymatic techniques may also be useful for the preparation of opticallyactive compounds and/or intermediates.

Similarly, when a pure regioisomer of a compound of the invention isrequired, it may be obtained by carrying out one of the above proceduresusing a pure regioisomer as a starting material, or by resolution of amixture of the regioisomers or intermediates using a standard procedure.

Biological Activity

According to a further feature of the invention there is provided acompound of the invention, or a pharmaceutically-acceptable salt, orin-vivo hydrolysable ester thereof for use in a method of treatment ofthe human or animal body by therapy.

According to a further feature of the present invention there isprovided a method for producing an antibacterial effect in a warmblooded animal, such as man, in need of such treatment, which comprisesadministering to said animal an effective amount of a compound of thepresent invention, or a pharmaceutically-acceptable salt, or in-vivohydrolysable ester thereof.

The ability of the invention compounds disclosed herein to achieve anantibacterial effect is demonstrated by the following tests.

Enzyme Potency Testing Methods

Supercoiling Assay Description:

Compounds were tested for inhibition of Escherichia coli DNAsupercoiling activity as follows. Assays were performed in polypropylenemultiwell plates in 50 μl reactions containing 35 mM Tris-HCl (pH 7.5),24 mM KCl, 4 mM MgCl₂, 2 mM dithiothreitol, 1.8 mM spermidine, 5% (v/v)glycerol, 200 nM bovine serum albumin, 1.25% (v/v) DMSO, 3 mM ATP, 10ng/ml relaxed pBR322 plasmid, 0.6 nM DNA gyrase, and test compound.Reactions were quenched after 1 hour by the addition of 10 μl of 30%(w/v) Ficoll-400, 10 mM EDTA, and 5% sodium dodecyl sulfate. Twenty-fiveμl of each sample was loaded onto a 0.8% (w/v) agarose gel andelectrophoresed. The gel and gel buffer contained 1×TBE buffer (89 mMTris base, 89 mM boric acid, and 2 mM EDTA at pH 8.3). Afterelectrophoresis for 3 hours at 70V, the gel was stained with ethidiumbromide and visualized by excitation with ultraviolet light. Thefluorescence intensity of the most supercoiled plasmid band was used tomeasure gyrase activity. Compound potency was based IC₅₀ measurementsdetermined from reactions performed with eight 2-fold serial dilutionsof each compound and a control without compound.

Compounds of the Examples generally have an IC₅₀ of <20 μg/ml.

ATPase Assay Description:

Compounds were tested for inhibition of GyrB ATPase activity using anammonium molybdate/malachite green-based phosphate detection assay(Lanzetta, P. A., L. J. Alvarez, P. S. Reinach, and O. A. Candia, 1979,100: 95-97). Assays were performed in multiwell plates in 100 μlreactions containing: 50 mM TRIS buffer pH 7.5, 75 mM ammonium acetate,5.5 mM magnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5%glycerol, 1 mM 1,4-dithio-DL-threitol, 200 nM bovine serum albumin, 16μg/ml sheared salmon sperm DNA, 4 nM E. coli GyrA, 4 nM E. coli GyrB,250 μM ATP, and compound in dimethylsulfoxide. Reactions were quenchedwith 150 μL of ammonium molybdate/malachite green detection reagentcontaining 1.2 mM malachite green hydrochloride, 8.5 mM ammoniummolybdate tetrahydrate, and 1 M hydrochloric acid. Plates were read inan absorbance plate reader at 625 nm and percent inhibition values werecalculated using dimethylsulfoxide (2%)-containing reactions as 0%inhibition and novobiocin-containing (2 μM) reactions as 100% inhibitioncontrols. Compound potency was based on IC₅₀ measurements determinedfrom reactions performed in the presence of 10 different compoundconcentrations.

Compounds of the invention generally have an IC₅₀ of <20 μg/ml.

Bacterial Susceptibility Testing Methods

Compounds were tested for antimicrobial activity by susceptibilitytesting in liquid media in a 96 well format. Compounds were dissolved indimethylsulfoxide and tested in 10 doubling dilutions in thesusceptibility assays. The organisms used in the assay were grownovernight on suitable agar media and then suspended in a liquid mediumappropriate for the growth of the organism. The suspension was a 0.5McFarland and a further 1 in 10 dilution was made into the same liquidmedium to prepare the final organism suspension in 100 μL. Plates wereincubated under appropriate conditions at 37° C. for 24 hours prior toreading. The Minimum Inhibitory Concentration (MIC) was determined asthe lowest drug concentration able to reduce growth by 80% or more.

Compounds were evaluated against a panel of Gram-positive species,including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcuspyogenes, and Enterococcus faecium. In addition, compounds wereevaluated against a panel of Gram-negative species including Haemophilusinfluenzae, Escherichia coli and Moraxella catarrhalis. Compounds of thepresent invention have MIC's less than or equal to 8 μg/ml versus one ormore of the organisms named above.

Data for several compounds of the invention are depicted below:

gyrase ATPase gyrase E. coli MIC S. pneumo [microgram/ supercoiling[microgram/ [microgram/ Example ml] [microgram/ml] ml] ml] 5 0.07 0.0510.5 0.12 66 0.3 ND 4 8 37 0.008 ND 0.25 0.06 26 ND 0.42 1 0.25 49 ND 3 84Pharmaceutical Formulations

In another embodiment the present invention provides a pharmaceuticalcomposition which comprises a compound of formula (I) admixed with apharmaceutically-acceptable carrier, diluent, or excipient.

The invention compositions may be in a form suitable for oral use (forexample as tablets, lozenges, hard or soft capsules, aqueous or oilysuspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration aseye-drops, for administration by inhalation (for example as a finelydivided powder or a liquid aerosol), for administration by insufflation(for example as a finely divided powder) or for parenteraladministration (for example as a sterile aqueous or oily solution forintravenous, subcutaneous, sub-lingual, intramuscular or intramusculardosing or as a suppository for rectal dosing).

In addition to the compounds of the present invention, thepharmaceutical composition of this invention may also contain (i.e.through co-formulation) or be co-administered (simultaneously,sequentially or separately) with one or more known drugs selected fromother clinically useful antibacterial agents (for example, β-lactams,macrolides, quinolones or aminoglycosides) and/or other anti-infectiveagents (for example, an antifungal triazole or amphotericin). These mayinclude carbapenems, for example meropenem or imipenem, to broaden thetherapeutic effectiveness. Compounds of this invention may also beco-formulated or co-administered withbactericidal/permeability-increasing protein (BPI) products or effluxpump inhibitors to improve activity against gram negative bacteria andbacteria resistant to antimicrobial agents.

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical diluents, carriers, orexcipients, well known in the art. Thus, compositions intended for oraluse may contain, for example, one or more coloring, sweetening,flavoring and/or preservative agents. A pharmaceutical composition to bedosed intravenously may contain advantageously (for example to enhancestability) a suitable bactericide, antioxidant or reducing agent, or asuitable sequestering agent.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),coloring agents, flavoring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavoring and coloring agents,may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil in water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol. Solubility enhancing agents,for example cyclodextrins may be used.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. A suitable pharmaceutical composition of this inventionis one suitable for oral administration in unit dosage form. Forexample, a formulation intended for oral administration to humans willgenerally contain, for example, a therapeutically effective amount ofactive agent compounded with an appropriate and convenient amount ofexcipients which may vary from about 1 to about 98 percent by weight ofthe total composition. For further information on Routes ofAdministration and Dosage Regimes the reader is referred to Chapter 25.3in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

In another aspect a pharmaceutical composition of the invention is onesuitable for intravenous, subcutaneous or intramuscular injection. Eachpatient may receive, for example, a daily intravenous, subcutaneous orintramuscular dose of a compound of this invention, the compositionbeing administered 1 to 4 times per day. The intravenous, subcutaneousand intramuscular dose may be given by means of a bolus injection.Alternatively, the intravenous dose may be given by continuous infusionover a period of time. Alternatively, each patient may receive a dailyoral dose which may be approximately equivalent to the daily parenteraldose, the composition being administered 1 to 4 times per day.

EXAMPLES

The invention will now be illustrated by the following non-limitingexamples.

Example 11-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxyquinolin-2(1H)-one

A solution of1-[2-(4-aminopiperidin-1-yl)ethyl]-7-methoxyquinolin-2(1H)-one(Intermediate 1, crude, 60 mg, 0.20 mmol) and2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(33 mg, 0.20 mmol) in dry chloroform/methanol (5 mL, 1:1) was heatedover 3 Å molecular sieves at 70° C. for 3 hours. The reaction mixturewas cooled to 0° C., and sodium triacetoxy borohydride (127 mg, 0.6mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 30 minutes and then was filtered through a 0.45 μmmembrane and concentrated to dryness under reduced pressure. The residuewas taken up in dichloromethane (50 mL) and saturated aqueous sodiumhydrogen carbonate solution (5 mL). The pH of the aqueous phase wasadjusted to a pH of 10 with 1M aqueous sodium hydroxide solution. Theaqueous phase was back extracted twice with dichloromethane (2×20 mL)and the combined organic phases were dried over sodium sulfate andconcentrated under reduced pressure. Chromatography on silica gel withdichloromethane/methanol (8:1 to 4:1) gave the free base of the titlecompound as a colorless oil. The free base was taken up indichloromethane (2 mL), ethanol (7 mL) was added, followed by additionof 1M HCl in ether (0.3 mL). The colorless precipitate was collected byfiltration and gave 50 mg (48%) of the bis-hydrochloride salt of theproduct, mp 243° C.

MS (ES): 451.14 (MH⁺) for C₂₅H₃₀N₄O₄

¹H-NMR (DMSO-d₆) δ (ppm): 2.00-3.80 (m, 11H); 3.96 (s, 3H); 4.20-4.45(m, 6H); 4.68 (m, 2H); 6.45 (d, 1H); 6.93 (d, 1H); 7.18 (s, 1H); 7.30(s, 1H); 7.68 (d, 1H); 8.25 (s, 1H); 9.74 (brs, 2H); 11.18 (brs, 1H).

Intermediate 1:1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxyquinolin-2(1H)-one

A solution of tert-butyl{1-[2-(7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 2, 150 mg, 0.37 mmol) in dioxane (4 mL) was treated atroom temperature under vigorous stirring with a solution of HCl indioxane (4M, 2 mL). After 18 hours, the reaction mixture wasconcentrated under reduced pressure. The residue was taken up indichloromethane (60 mL) and saturated aqueous sodium hydrogen carbonatesolution (10 mL). The aqueous phase was extracted three times withdichloromethane (3×50 mL) and the combined organic phases were driedover sodium sulfate and concentrated under reduced pressure to give 113mg (100% yield) of the crude product as an oil.

MS (ES): 302.24 (MH⁺) for C₁₇H₂₃N₃O₂

¹H-NMR (DMSO-d₆) δ: 1.21 (m, 2H); 1.65 (in, 2H); 2.04 (t, 2H); 2.40-2.52(m, 2H); 2.89 (m, 2H); 3.69 (m, 1H); 3.88 (s, 3H); 4.31 (t, 2H); 6.40(m, 1H); 6.88 (m, 1H); 6.94 (m, 1H); 7.63 (m, 1H); 7.80 (m, 1H). (TheNH₂ protons were not observed)

Intermediate 2:tert-Butyl{1-[2-(7-methoxy-2-oxoquinolin-1-(2H)-yl-ethyl]piperidin-4-yl}carbamate

A solution of 7-methoxyquinolin-2(1H)-one (Intermediate 3, 340 mg, 2.2mmol) in dry dimethylformamide (DMF) (10 mL) was treated at 0° C. with acooling bath under stirring with sodium hydride (88 mg, 60% in oil, 2.2mmol). The cooling bath was removed and the mixture was stirred for 30minutes at room temperature. A solution of2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonatein N,N-dimethylformamide (DMF) (Intermediate 6, 0.58 mmol/mL, 3.5 mL,2.03 mmol) was then added and the resulting mixture was stirred overnight at room temperature. Thin Layer Chromatography (TLC): Rf=0.1(hexanes/acetone, 1:1) (the O-alkylated product was observed as a minorproduct and has a rf value of 0.3). The DMF was removed under reducedpressure, and the residue was taken up in ethyl acetate (100 mL) andsaturated aqueous sodium hydrogencarbonate solution (30 mL). The aqueousphase was back extracted once with ethyl acetate (50 mL). The combinedorganic phases were dried over sodium sulfate and concentrated underreduced pressure. Chromatography on silica gel with hexanes/acetone(1:1) gave 153 mg (20% yield) of the product as a colorless hard foam.

MS (ES): 402.25 (MH⁺) for C₂₂H₃₁N₃O₄

¹H-NMR (DMSO-d₆) δ: 1.30-1.42 (m, 2H); 1.36 (s, 9H); 1.66 (m, 2H); 2.04(m, 2H); 2.45-2.53 (m, 2H); 2.92 (m, 2H); 3.15 (m, 1H); 3.88 (s, 3H);4.31 (t, 2H); 6.39 (m, 1H); 6.76 (m, 1H); 6.88 (m, 1H); 6.93 (m, 1H);7.62 (d, 1H); 7.80 (d, 1H). (The structure was confirmed by an HMBC-NMRexperiment)

Intermediate 3: 7-Methoxyquinolin-2(1H)-one

A solution of methyl (2E)-3-(2-amino-4-methoxyphenyl)acrylate(Intermediate 4, 500 mg, 2.4 mmol) in acetonitrile (600 mL) wasdeoxygenated under vacuum, purged with nitrogen and irradiated at 365 nmwith a long wave UV lamp (B-100AP, Blak Ray) for 28 hours. The solventwas removed under reduced pressure and the product was precipitated fromdichloromethane (20 mL) by the addition of hexanes (100 mL) to give 357mg (76% yield) of the crude product as a colorless solid, 90% pure by¹H-1-NMR (together with 10% dimer), mp 190° C.

MS (ES): 176.21 (MH⁺) for C₁₀H₉NO₂

¹H-NMR (DMSO-d₆) δ: 3.79 (s, 3H); 6.28 (d, 1H); 6.75-6.81 (m, 2H); 7.55(d, 1H); 7.79 (d, 1H); 11.59 (s, 1H).

Intermediate 4: Methyl (2E)-3-(2-amino-4-methoxyphenyl)acrylate

To a solution of methyl (2E)-3-(4-methoxy-2-nitrophenyl)acrylate(Intermediate 5, 4.9 g, 20.66 mmol) in acetic acid (150 mL) at roomtemperature under nitrogen was added zinc powder (7.7 g, 118 mmol) inportions. After 4 hours, another 5 g of zinc was added and the resultingreaction mixture was heated at 50° C. for two hours. The reactionmixture was then cooled to room temperature, filtered, and the filtratewas concentrated to dryness under reduced pressure. The residue waschromatographed on silica gel with hexanes/ethyl acetate (3:1) to give1.0 g (23% yield) of product as a yellow solid, mp 149° C.

MS (ES): 208.17 (MH⁺ for C₁₁H₁₃NO₃

¹H-NMR (DMSO-d₆) δ: 3.67 (s, 3H); 3.68 (s, 3H); 5.68 (brs, 2H); 6.14(dd, 1H); 6.21 (d, 1H); 6.23 (s, 1H); 7.40 (d, 1H); 7.82 (d, 1H).

Intermediate 5: (2E)-3-(4-Methoxy-2-nitrophenyl)acrylate

A solution of 4-iodo-3-nitroanisole (10 g, 36 mmol), methylacrylate(3.87 mL, 43 mmol), tris(4-methylphenyl)phosphine (1.1 g, 3.6 mmol) andtriethylamine (6.05 mL, 43 mmol) was degassed and flushed with nitrogen.Palladium(II) acetate (1.2 g, 1.8 mmol) was added and the mixture washeated at 70° C. overnight. It was filtered through a 0.45 μm membraneand the solvent was removed under reduced pressure. The residue wastaken up in ethyl acetate (300 mL), it was washed with potassiumphosphate buffer (1M, pH 7, 2×300 mL) and dried over sodium sulfate.Chromatography on silica gel with dichloromethane, followed byprecipitation from dichloromethane (50 mL) with hexanes (500 mL) gave4.96 g (58% yield) of product as a yellow solid.

MS (ES): 260.20 (MNa⁺) for C₁₁H₁₁NO₅

¹H-NMR (DMSO-d₆) δ: 3.73 (s, 3H); 3.88 (s, 3H); 6.59 (d, 1H); 7.33 (dd,1H); 7.57 (d, 1H); 7.78 (d, 1H); 7.94 (d, 1H).

Intermediate 6: 2-{4-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}ethylmethanesulfonate

A mixture of tert-butyl [1-(2-hydroxyethyl)piperidin-4-yl]carbamate(Intermediate 7, 1.7 g, 7 mmol) in dry dichloromethane (20 mL) andtriethyl amine (1.4 mL, 9.8 mmol) was treated at 0° C. withmethanesulfonyl chloride (0.65 mL, 8.4 mmol). After 45 minutes thereaction was complete by TLC (chloroform/methanol 6:1, rf 0.54).Potassium phosphate buffer (pH 7, 1M, 50 mL) was added, dichloromethanewas removed under reduced pressure and it was extracted with ice-coldethyl acetate (2×100 mL) and dried over sodium sulfate. The solvent wasremoved under reduced pressure and the crude preparation of the mesylatewas used without delay for the next step.

MS (ES): 323.18 (MH⁺) for C₁₃H₂₆N₂O₅S

Intermediate 7: tert-Butyl[1-(2-hydroxyethyl)piperidin-4-yl]carbamate

A mixture of tert-butyl piperidin-4-ylcarbamate (5 g, 25 mmol),2-bromoethanol (1.77 mL, 25 mmol) and triethylamine (3.86 mL, 27.5 mmol)in acetonitrile (20 mL) was heated in a sealed tube at 50° C. for 16hours. The solvent was removed under reduced pressure, and the residuewas taken up in ethyl acetate (300 mL) and washed with saturated aqueoussodium hydrogen carbonate solution (100 mL). The aqueous phase wasback-extracted once with ethyl acetate (100 mL) and the combined organicphases were dried over sodium sulfate and concentrated under reducedpressure. Chromatography on silica gel with dichloromethane/methanol(4:1) gave 4.04 g (66% yield) of product as a colorless solid, mp 66° C.

MS (ES): 245.28 (MH⁺) for C₁₂H₂₄N₂O₃

¹H-NMR (DMSO-d₆) δ: 1.33 (m, 2H); 1.36 (s, 9H); 1.62 (m, 2H); 1.92 (t,2H); 2.32 (t, 2H); 2.77 (m, 2H); 3.17 (m, 1H); 3.43 (m, 2H); 4.34 (t,1H); 6.73 (d, 1H).

Example 21-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxyquinolin-4(1H)-one

A solution of1-[2-(4-aminopiperidin-1-yl)ethyl]-7-methoxyquinolin-4(1H)-one(Intermediate 8, 60 mg, 0.20 mmol) and2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(33 mg, 0.20 mmol) in dry chloroform/methanol (5 mL, 1:1) was heatedover 3 Å molecular sieves at 70° C. for 3 hours. The reaction mixturewas cooled to 0° C., and sodium triacetoxyborohydride (127 mg, 0.6 mmol)was added and the resulting mixture was stirred at room temperature for30 minutes. The mixture was then filtered through a 0.45 μm membrane,acidified with conc. HCl to pH 1 and concentrated to dryness underreduced pressure. The residue was taken up in dichloromethane (50 mL)and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pHof the aqueous phase was adjusted to pH10 with 1M aqueous sodiumhydroxide solution. The aqueous phase was back extracted twice withdichloromethane (2×20 mL) and the combined organic phases were driedover sodium sulfate. Chromatography on silica gel withdichloromethane/methanol (4:1), containing 0.125% ammonium hydroxide,gave the free base of the title compound as a colorless oil. The freebase was taken up in dichloromethane (2 mL), ethanol (7 mL) was added,followed by addition of 1M HCl in ether (0.45 mL). The colorlessprecipitate was collected by filtration and gave 84 mg (81% yield) ofthe bis-hydrochloride salt of the product, mp 260° C.

MS (ES): 451.21 (MH⁺) for C₂₅H₃₀H₄O₄

¹H-NMR (DMSO-d₆) δ: 2.00-3.80 (m, 11H); 4.07 (s, 3H); 4.30-4.46 (m, 6H);5.06 (m, 2H); 6.83 (d, 1H); 7.28 (d, 1H); 7.45-7.58 (m, 2H); 8.22 (d,1H); 8.37 (s, 1H); 8.61 (d, 1H); 9.94 (brs, 2H); 11.90 (brs, 1H).

Intermediate 8:1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxyquinolin-4(1H)-one

A mixture of tert-butyl{1-[2-(7-methoxy-4-oxoquinolin-1(4H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 9, 370 mg, 0.92 mmol) in dioxane (10 mL) was treated atroom temperature under vigorous stirring with a solution of HCl indioxane (4M, 4 mL). After 18 hours, the reaction mixture was dilutedwith isopropanol (10 mL) and with water (4 mL) and more HCl in dioxane(4M, 5 mL) was added. After 1 hour, the reaction mixture wasconcentrated under reduced pressure to give the hydrochloride of theproduct as a colorless solid. The hydrochloride salt was taken up inaqueous sodium hydroxide solution (1M, 10 mL) and extracted withdichloromethane (60 mL). The aqueous phase was extracted three timeswith dichloromethane (3×60 mL) and the combined organic phases weredried over sodium sulfate to give 278 mg (100% yield) of the crudeproduct as an oil.

MS (ES): 302.24 (MH⁴) for C₁₇H₂₃N₃O₂

¹H-NMR (DMSO-d₆) (data for the hydrochloride salt) δ: 1.80-2.30 (m, 4H);3.14 (m, 2H); 3.36 (m, 1H); 3.48 (m, 2H); 3.68 (m, 2H); 4.06 (s, 3H);5.03 (m, 2H); 6.74 (d, 1H); 7.24 (d, 1H); 7.45 (s, 1H); 8.21 (d, 1H);8.46 (brs, 2H); 8.55 (d, 1H); 8.60 (brs, 1); 11.95 (brs, 1H).

Intermediate 9: tert-Butyl{1-[2-(7-methoxy-4-oxoquinolin-1(4H)-yl)ethyl]piperidin-4-yl}carbamate

A solution of 7-methoxyquinolin-4-ol (Intermediate 10, 500 mg, 2.85mmol) in dry DMF (10 mL) was treated at 0° C. with a cooling bath understirring with sodium hydride (114 mg, 60% in oil, 2.85 mmol). Thecooling bath was removed and the mixture was stirred for 30 minutes atroom temperature. A solution of2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonatein DMF (Intermediate 6, 0.58 mmol/mL, 5 mL, 2.9 mmol) was added and theresulting solution was stirred over night at room temperature. DMF wasremoved under reduced pressure, the residue was taken up in ethylacetate (100 mL) and saturated aqueous sodium hydrogen carbonatesolution (30 mL) and the aqueous phase was back extracted three timeswith ethyl acetate (3×70 mL). The combined organic phases were driedover sodium sulfate. Some starting 7-methoxyquinolin-4-ol wasprecipitated from dichloromethane (30 mL) with hexanes (20 mL) andremoved by filtration. The filtrate was concentrated to dryness underreduced pressure. Chromatography of the residue on silica gel withacetonitrile/water (15:1 to 10:1) gave 373 mg (33% yield) of the productas a colorless solid, mp 207° C.

MS (ES): 402.36(MH⁺) for C₂₂H₃₁N₃O₄

¹H-NMR (DMSO-d₆) δ: 1.25-1.37 (m, 2H); 1.35 (s, 9H); 1.63 (m, 2H); 2.02(m, 2H); 2.60 (t, 2H); 2.82 (m, 2H); 3.16 (m, 1H); 3.89 (s, 3H); 4.28(t, 2H); 5.92 (d, 1H); 6.75 (d, 1H); 6.96 (dd, 1H); 7.00 (d, 1H); 7.82(d, 1H); 8.06 (d, 1H).

Intermediate 10: 7-Methoxyquinolin-4-ol

5-{[(3-Methoxyphenyl)amino]methylene}-2,2-dimethyl-1,3-dioxane-4,6-dione(Intermediate 11, 43.5 g, 157 mmol) was added in small portions tophenylether (200 mL) at 225-260° C. under stirring. The reaction mixturewas stirred for an additional 5 minutes, until the evolution of gas hadstopped. The reaction mixture was cooled to room temperature and theprecipitate was collected by filtration and washed with hexanes.Purification by recrystallization from methanol gave 12.4 g (45% yield)of product as a green solid, mp 210° C.

MS (ES): 176.21 (MH⁺) for C₁₀H₉NO₂.

¹H-NMR (DMSO-d₆) δ: 3.83 (s, 3H); 5.93 (d, 1H); 6.85-6.95 (m, 2H); 7.80(m, 1H); 7.97 (d, 1H); 11.55 (brs, 1H).

Intermediate 11:5-{[(3-Methoxyphenyl)amino]methylene}-2,2-dimethyl-1,3-dioxane-4,6-dione

A mixture of m-anisidine (22 g, 178 mmol),2,2-dimethyl-1,3-dioxane-4,6-dione (30.75 g, 214 mmol) andtriethylorthoformate (30 mL, 178 mmol) in ethanol (200 mL) was heated at85° C. for two hours. The mixture was allowed to cool to roomtemperature and the precipitate was collected by filtration and washedwith ethanol to give 43.7 g (89% yield) of product as a pale yellowsolid, mp 108° C.

MS (ES): 276.12 (M-H⁻) for C₁₄H₁₅NO₅

¹H-NMR (DMSO-d₆) δ: 1.66 (s, 6H); 3.78 (s, 3H); 6.81 (d, 1H); 7.09 (d,1H); 7.19 (m, 1H); 7.32 (dd, 1H); 8.59 (d, 1H); 11.19 (d, 1H).

Example 3 Methyl1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methoxy-1H-indole-2-carboxylate

A solution of methyl1-[2-(4-aminopiperidin-1-yl)ethyl]-6-methoxy-1H-indole-2-carboxylate(Intermediate 12, 200 mg, 0.60 mmol) and2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(100 mg, 0.60 mmol) in dry chloroform/methanol (10 mL, 1:1) was heatedover 3 Å molecular sieves at 70° C. for 3 hours. The reaction mixturewas cooled to 0° C., sodium triacetoxy borohydride (384 mg, 1.8 mmol)was added and the resulting mixture was stirred at room temperature for30 minutes. The reaction mixture was filtered through a 0.45 μm membraneand concentrated to dryness under reduced pressure. The residue wastaken up in dichloromethane (150 mL) and saturated aqueous sodiumhydrogen carbonate solution (30 mL), the aqueous phase back extractedonce with dichloromethane (70 mL) and the combined organic phases weredried over sodium sulfate. Chromatography on silica gel withdichloromethane/methanol (5:1), containing 0.125% ammonium hydroxide,gave the free base of the title compound, 239 mg (82% yield), as acolorless solid, mp 130° C.

MS (ES): 481.15 (MH⁺) for C₂₆H₃₂N₄O₅

¹H-NMR (DMSO-d₆) δ: 1.10-1.25 (m, 2H); 1.70 (m, 2H); 1.96 (t, 2H); 2.12(m, 1H); 2.30 (m, 2H); 2.79 (m, 2H); 3.62 (s, 2H); 3.80 (s, 3H); 3.82(s, 3H); 4.22-4.35 (m, 4H); 4.58 (t, 2H); 6.75 (m, 1H); 6.91 (s, 1H);7.01 (s, 1H); 7.17 (s, 1H); 7.52 (d, 1H); 7.98 (s, 1H).

Intermediate 12: Methyl1-[2-(4-aminopiperidin-1-yl)ethyl]-6-methoxy-1H-indole-2-carboxylate

A solution of methyl1-(2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl)-6-methoxy-1H-indole-2-carboxylate(Intermediate 13, 520 mg, 1.2 mmol) in dioxane (4 mL) was treated atroom temperature under vigorous stirring with a solution of HCl indioxane (4M, 2 mL). After 3 days, the reaction mixture was concentratedunder reduced pressure. The residue was taken up in dichloromethane (60mL) and saturated aqueous sodium hydrogen carbonate solution (10 mL),the aqueous phase was extracted three times with dichloromethane (3×50mL) and the combined organic phases were dried over sodium sulfate togive 407 mg (100% yield) of the crude product as colorless solid, mp101° C.

MS (ES); 332.23 (MH⁺) for C₁₈H₂₅N₃O₃

¹H-NMR (DMSO-d₆) δ: 1.15 (m, 2H); 1.61 (m, 2H); 1.99 (t, 2H); 2.51 (m,2H); 2.79 (m, 2H); 3.49 (m, 1H); 3.81 (s, 3H); 3.83 (s, 3H); 4.59 (t,2H); 6.76 (m, 1H); 7.02 (brs, 1H); 7.18 (s, 1H); 7.53 (d, 1H). (The NH₂protons were not observed)

Intermediate 13: Methyl1-(2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl)-6-methoxy-1H-indole-2-carboxylate

A solution of methyl 6-methoxy-2-indole-carboxylate (574 mg, 2.8 mmol)in dry DMF (10 mL) was treated at 0° C. with a cooling bath understirring with sodium hydride (123 mg, 60% in oil, 3.08 mmol). Thecooling bath was removed and the mixture was stirred for 30 minutes atroom temperature. A solution of2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonatein DMF (Intermediate 6, 0.58 mmol/mL, 3.4 mL, 2.0 mmol) was added andthe resulting mixture was stirred over night at room temperature. TheDMF was removed under reduced pressure, the residue was taken up inethyl acetate (100 mL) and saturated aqueous sodium hydrogencarbonatesolution (30 mL) and the aqueous phase was back extracted once withethyl acetate (70 mL). The combined organic phases were dried oversodium sulfate. Chromatography on silica gel with hexanes/ethyl acetate(1:1 to pure ethyl acetate) gave 523 mg (43% yield) of the product as acolorless solid, mp 158° C.

MS (ES): 432.25 (MH⁺) for C₂₃H₃₃N₃O₅

¹H-NMR (DMSO-d₆) δ: 1.23-1.37 (m, 2H); 1.35 (s, 9H); 1.63 (m, 2H); 1.99(t, 2H); 2.51 (m, 2H); 2.81 (m, 2H); 3.15 (m, 1H); 3.81 (s, 3H); 3.83(s, 3H); 4.58 (t, 2H); 6.72-6.78 (m, 2H); 7.01 (brs, 1H); 7.17 (s, 1H);7.53 (d, 1H).

Example 46-[({1-[2-(7-Methoxy-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxyquinolin-2(1H)-one(Intermediate 1, crude, 60 mg, 0.20 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (43 mg, 0.24 mmol) in dry dichloroethane/methanol (10 mL,1:1) were heated over 3 Å molecular sieves at reflux for 4 hours. Thereaction mixture was cooled to 0° C., and sodium cyanoborohydride (19mg, 0.30 mmol) was added and it was stirred at room temperature for 2hours. The mixture was filtered through a fritted funnel andconcentrated to dryness under reduced pressure. The residue was taken upin ethyl acetate and washed with saturated sodium bicarbonate followedby saturated sodium chloride. The saturated sodium bicarbonate wasextracted with chloroform, and the chloroform was washed with saturatedsodium chloride. The ethyl acetate and chloroform extracts werecombined, dried over sodium sulfate and concentrated to dryness underreduced pressure. Silica gel chromatography withdichloromethane/methanol/ammonia ammonia (8:2:0.01) gave title compoundas a colorless oil, 27 mg (30%).

MS (ES): 464.34 (MH⁺) for C₂₅H₂₉N₅O₄

¹H-NMR (CDCl₂-d₆) δ: 1.93 (m, 4H); 2.94 (m, 3H); 3.38 (m, 2H); 3.48 (s,2H); 4.02 (m, 6H); 4.64 (s, 2H); 4.66 (m, 1H); 6.51 (d, J=9.4 Hz, 1H);6.83 (dd, J=6.5, 2.1 Hz, 1H); 7.22 (d, J=8.1 Hz, 1H); 7.46 (m, 2H); 7.62(m, 2H).

Example 51-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile

1-[2-(4-Aminopiperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile(Intermediate 14, 70 mg, 0.24 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(40 mg, 0.24 mmol) and sodium triacetoxy borohydride (150 mg, 0.75 mmol)were reacted as described for Example 1, but the aqueous workup wasomitted. Chromatography on silica gel with dichloromethane/methanol(6:1) and crystallization from dichloromethane/ether/hexanes gave themonoacetate salt of the product as a colorless solid, 69 mg (58%), mp130-135° C.

MS (ES): 446.24 (MH⁺) for C₂₅H₂₇N₅O₃

¹H-NMR (DMSO-d₆) δ: 1.19 (m, 2H); 1.73 (m, 2H); 1.89 (s, 3H); 2.00 (t,2H); 2.34 (m, 1H); 2.51 (m, 2H, under solvent peak); 2.88 (m, 2H); 3.65(s, 2H); 4.24-4.37 (m, 6H); 6.76 (d, 1H); 6.92 (s, 1H); 7.63 (dd, 1H);7.90 (d, 1H); 7.97-8.00 (m, 2H); 8.07 (brs, 1H).

Intermediate 14:1-[2-(4-Aminopiperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile

A solution of tert-butyl{1-[2-(7-cyano-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 15) (6.57 g, 16.57 mmol) in dichloromethane (100 mL) wastreated with trifluoroacetic acid (40 mL) at 0° C. for 30 minutes. Thesolvent was removed under reduced pressure and the residue codistilledonce with dichloromethane, then taken up in dichloromethane (200 mL) andwashed with saturated sodium hydrogencarbonate solution (50 mL, pHadjusted to 10 with sodium hydroxide). The aqueous phase wasback-extracted three times with dichloromethane (3×100 mL) and driedover sodium sulfate. The solvent was removed under reduced pressure togive the product as off-white solid, 5 g, mp 138° C.

MS (ES): 296.91 (MH⁺) for C₁₇H₂₀N₄O

¹H-NMR (DMSO-d₆) δ: 1.13 (m, 2H); 1.48 (m, 1H); 1.62 (m, 2H); 2.01 (t,2H); 2.50 (m, 2H, under solvent peak); 2.86 (m, 2H); 4.35 (t, 2H); 6.76(d, 1H); 7.63 (d, 1H); 7.90 (d, 1H); 7.98 (d, 1H); 8.07 (s, 1H).

Intermediate 15: tert-Butyl{1-[2-(7-cyano-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

A mixture of tert-butyl{1-[2-(7-bromo-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 16) (9.85 g, 21.9 mmol) and potassium cyanide (2.14 g,32.8 mmol) in dry acetonitrile (60 mL) was degassed and flushed withnitrogen three times. Tributyltinchloride (0.059 mmol, 1.13 mL of a 51.6mM solution in heptane) was added, followed by4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63 mg, 0.11 mmol) andtris(dibenzylideneacetone)dipalladium (0) (100 mg, 0.11 mmol) and it wasdegassed and flushed with nitrogen like above. The mixture was stirredfor 30 minutes at room temperature and then degassed and flushed withnitrogen again. It was heated at 85° C. for 20 hours. The solvent wasremoved under reduced pressure and the residue taken up indichloromethane (500 mL) and washed with water (200 mL). The aqueousphase was back-extracted once with dichloromethane (200 mL) and combinedorganic phases were dried over sodium sulfate. Solvent was removed underreduced pressure and the residue was crystallized from acetonitrile (60mL) to give the product as a colorless solid, 6.57 g (76%), mp 202° C.

MS (ES): 397.21 (MH⁺) for C₂₂H₂₈N₄O₃

¹H-NMR (DMSO-d₆) δ: 1.30 (m, 2H); 1.36 (s, 9H); 1.64 (m, 2H); 2.02 (m,2H); 2.50 (m, 2H, under solvent peak); 2.90 (m, 2H); 3.15 (m, 1H); 4.34(t, 2H); 6.74-6.78 (m, 2); 7.63 (m, 1H); 7.89 (d, 1H); 7.99 (d, 1H);8.05 (s, 1H).

Intermediate 16: tert-Butyl{1-[2-(7-bromo-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

7-Bromoquinolin-2(1H)-one (Intermediate. 17) (7.4 g, 33 mmol) wasdeprotonated with sodium hydride (1.45 g, 60% in oil, 36 mmol) andalkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethylmethanesulfonate (Intermediate 6) (40 mmol) as described forIntermediate 2; Chromatography on silica gel with hexanes/acetone (5:2)gave 9.87 g (66%) of the product as a colorless solid, mp 155° C.

MS (ES): 450\452 (MH⁺) for C₂₁H₂₈BrN₃O₃

¹H-NMR (DMSO-d₆) δ: 1.32 (m, 2H); 1.36 (s, 9H); 1.65 (m, 2H); 2.01 (t,2H); 2.46 (m, 2H); 2.90 (m, 2H); 3.19 (m, 1H); 4.29 (t, 2H); 6.61 (d,1H); 6.75 (d, 1H); 7.41 (d, 1H); 7.65 (d, 1H); 7.73 (brs, 1H); 7.89 (d,1H).

Intermediate 17: 7-Bromoquinolin-2(1H)-one

(2E)-N-(3-bromophenyl)-3-phenylacrylamide (Intermediate 18) (16 g, 53mmol) and aluminium trichloride (31.8 g, 238 mmol) were heated inchlorobenzene (100 mL) at 90° C. bath temperature for one hour. Thereaction mixture was cooled to room temperature and poured onto ice. Itwas stirred until the ice was completely melted, the mixture wasfiltered and washed with water and ethyl acetate to give the crudeproduct as slightly brown solid in a mixture with the minor product5-bromoquinolin-2(1H)-one (3:2), 8.8 g (70%). This mixture could not beseparated. The mixture was heated in phosphoroxychloride (50 mL) at 65°C. for one hour. The reaction mixture was cooled to room temperature andpoured onto ice. It was carefully neutralized at 0° C. with sodiumcarbonate, extracted into ethyl acetate (300 mL), washed with brine,dried over sodium sulfate and concentrated to give the crude mixture of7-bromo-2-chloroquinoline and 5-bromo-2-chloroquinoline. The mixture wastaken up in dichloromethane (100 mL), treated with silica gel (20 g),filtered and the filter cake was washed with dichloromethane. Filtrateand wash were combined and concentrated. The residue was crystallizedfrom toluene/hexanes (70 mL, 1:1) to provide pure7-bromo-2-chloroquinoline, 3.74 g as a colorless solid mp 113° C.

MS (ES): 242/244/246 (MH⁺) for C₉H₅BrClN

¹H-NMR (DMSO-d₆) δ: 7.63 (d, J 8.4 Hz, 1H); 7.81 (dd, J 8.4, 1.6 Hz,1H); 8.03 (d, J 8.4 Hz, 1H); 8.18 (d, J 1.6 Hz, 1H); 8.48 (d, J 8.4 Hz,1H).

7-Bromo-2-chloroquinoline was heated in 5M HCl (100 mL) and dioxane (10mL) for 1 hour at reflux. The Reaction mixture was cooled, filtered andwashed with water to give the title compound, 2.89 g, as a colorlesssolid, mp 295° C.

MS (ES): 224.13/226.13 (MH⁺) for C₉H₆BrNO

¹H-NMR (DMSO-d₆) δ: 6.51 (d, J 9.6 Hz, 1H); 7.32 (dd, J 8.6, 1.6 Hz,1H); 7.46 (d, J 1.6 Hz, 1H); 7.61 (d, J 8.6 Hz, 1H); 7.88 (d, J 9.6 Hz,1H); 11.80 (brs, 1H).

Intermediate 18: (2E)-N-(3-Bromophenyl)-3-phenylacrylamide

To a solution of 3-bromoaniline (13.1 mL, 120 mmol) in dichloromethane(100 mL) and 2,6-lutidine (21 mL, 180 mmol) at 0° C. was added asolution of cinnamoylchloride (20 g, 120 mmol) in dichloromethane (50mL) dropwise. The reaction mixture was allowed to reach room temperatureand was stirred for 2 hours. It was quenched with potassium phosphatebuffer (100 mL, 1M, pH 7) and stirred for 15 minutes. Dichloromethanewas removed under reduced pressure. The residue was extracted with ethylacetate. The organic phase was washed with phosphate buffer (200 mL),dried over sodium sulfate and concentrated to dryness. The residue wascrystallized from toluene/hexanes to give the product as colorless solid(33.4 g, 92%).

MS (ES): 302/304 (MH⁺) for C₁₅H₁₂BrNO

¹H-NMR (DMSO-d₆) δ: 6.79 (d, 1H); 7.23-7.70 (m, 9H); 8.07 (s, 1H); 10.38(s, 1H).

Example 62-Oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-1,2-dihydroquinoline-7-carbonitrile

1-[2-(4-Aminopiperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoline-7-carbonitrile(Intermediate 14, 70 mg, 0.24 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (42 mg, 0.24 mmol)and sodium triacetoxy borohydride (150mg, 0.75 mmol) were reacted as described for Example 5. Chromatographyon silica gel with dichloromethane/methanol (6:1) and crystallizationfrom ethyl acetate/hexanes gave the product as a colorless solid, 73 mg(67%), mp 212° C.

MS (ES): 459.37 (MH⁺) for C₂₅H₂₆N₆O₃

¹H-NMR (DMSO-d₆) δ: 1.19 (m, 2H); 1.74 (m, 2H); 2.01 (t, 2H); 2.35 (m,1H); 2.51 (m, 2H, under solvent peak); 2.88 (m, 2H); 3.65 (s, 2H); 4.35(t, 2H); 4.59 (s, 2H); 6.76 (d, 1H); 7.00 (d, 1H); 7.28 (d, 1H); 7.63(dd, 1H); 7.89 (d, 1H); 7.99 (d, 1H); 8.06 (brs, 1H); 11.08 (brs, 1H).

Example 76-[({1-[2-(7,8-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7,8-difluoroquinolin-2(1H)-one(Intermediate 19) (100 mg, 0.325 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (58 mg, 0.325 mmol) and sodium triacetoxy borohydride (207mg, 0.98 mmol) were reacted as described for Example 1, but the aqueousworkup was omitted, to give 107 mg of the mono acetate salt of theproduct after chromatography, as a colorless solid, mp 158-170° C.

MS (ES): 470.13 (MH⁺) for C₂₄H₂₅F₂N₅O₃

¹H-NMR (DMSO-d₆) δ: 1.20 (m, 2H); 1.75 (m, 2H); 1.89 (s, 3H); 2.03 (t,2H); 2.36 (m, 1H); 2.55 (m, 2H); 2.82 (m, 2H); 3.66 (s, 2H); 4.40 (m,2H); 4.59 (s, 2H); 6.60 (d, 1H); 7.00 (d, 1H); 7.28 (d, 1H); 7.34 (m,1H); 7.60 (m, 1H); 7.91 (d, 1H); 11.17 (brs, 1H).

Intermediate 19:1-[2-(4-Aminopiperidin-1-yl)ethyl]-7,8-difluoroquinolin-2(1H)-one

The title compound was obtained from tert-butyl{1-[2-(7,8-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 20) (412 mg, 1.01 mmol) by the procedure described forIntermediate 1, 316 mg (quantitative yield), as a colorless gum.

MS (ES): 308.29 (MH⁺) for C₁₆H₁₉F₂N₃O

¹H-NMR (DMSO-d₆) δ: 1.15 (m, 2H); 1.46 (m, 1H); 1.62 (m, 2H); 2.03 (t,2H); 2.53 (m, 2H, under solvent peak); 2.79 (m, 2H); 4.39 (m, 2H); 6.60(d, 1H); 7.34 (m, 1H); 7.59 (m, 1H); 7.91 (d, 1H).

Intermediate 20: tert-Butyl{1-[2-(7,8-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

7,8-Difluoroquinolin-2(1H)-one (Intermediate 21) (500 mg, 2.8 mmol) wasdeprotonated with sodium hydride (121 mg, 60% in oil, 3.04 mmol) andalkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethylmethanesulfonate (Intermediate 6) (3.3 mmol) as described forIntermediate 2. Chromatography on silica gel with hexanes/acetone 2:1gave the product as a colorless solid, 414 mg (37%).

MS (ES): 408.30 (MH⁺) for C₂₁H₂₇F₂N₃O₃

¹H-NMR (DMSO-d₆) δ: 1.32 (m, 2H); 1.36 (s, 9H); 1.65 (m, 2H); 2.04 (t,2H); 2.53 (m, 2H); 2.83 (m, 2H); 3.16 (m, 1H); 4.38 (m, 2H); 6.61 (d,1H); 6.75 (d, 1H); 7.34 (m, 1H); 7.60 (m, 1H); 7.91 (m, 1H).

Intermediate 21: 7,8-Difluoroquinolin-2(1H)-one

The compound was prepared from(2E)-N-(2,3-difluorophenyl)-3-phenylacrylamide (Intermediate 22) (7.4 g,28.5 mmol) and aluminium trichloride (19 g, 142 mmol) as described forIntermediate 17. The crude cyclization product was obtained as a singleregioisomer, which was used without further purification, 2 g lightbrown solid (37%).

MS (ES): 182.04 (MH⁺) for C₉H₅F₂NO

¹H-NMR (DMSO-d₆) δ: 6.51 (d, 1H); 7.22 (m, 1H); 7.52 (m, 1H); 7.91 (m,1H).

Intermediate 22: (2E)-N-(2,3-Difluorophenyl)-3-phenylacrylamide

The compound was prepared from 2,3-difluoroaniline (5 g, 38.7 mmol) andcinnamoylchloride (6.45 g, 38.7 mmol) in the presence of 2,6-lutidine(6.8 mL, 58 mmol) as described for Intermediate 18 to give a colorlesssolid, 7.4 g (74%).

MS (ES): 260.08 (MH⁺) for C₁₅H₁₁F₂NO

¹H-NMR (DMSO-d₆) δ: 7.05 (d, 1H); 7.14-7.22 (m, 2H); 7.40-7.50 (m, 3H);7.59-7.64 (m, 3H); 7.89 (m, 1H); 10.16 (brs, 1H).

Example 86-[({1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one(Intermediate 23) (100 mg, 0.325 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (58 mg, 0.325 mmol) and sodium triacetoxy borohydride (207mg, 0.98 mmol) were reacted as described for Example 6, to give 114 mgof the mono acetate salt of the product as a colorless solid, mp170-180° C.

MS (ES): 470.32 (MH⁺) for C₂₄H₂₅F₂N₅O₃

¹H-NMR (DMSO-d₆) δ: 1.20 (m, 2H); 1.74 (m, 2H); 1.89 (s, 3H); 2.00 (t,2H); 2.36 (m, 1H); 2.48 (m, 2H); 2.88 (m, 2H); 3.66 (s, 2H); 4.29 (t,2H); 4.59 (s, 2H); 6.61 (d, 1H); 7.00 (d, 1H); 7.18-7.33 (m, 3H); 7.96(d, 1H); 11.16 (brs, 1H).

Intermediate 23:1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one

The title compound was obtained from tert-butyl{1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 24) (637 mg, 1.01 mmol) by the procedure described forIntermediate 1, 483 mg (quantitative), as a colorless solid.

MS (ES): 308.27 (MH⁺) for C₁₆H₁₉F₂N₃O

¹H-NMR (DMSO-d₆) δ: 1.15 (m, 2H); 1.46-1.64 (m, 3H); 2.00 (t, 2H); 2.46(m, 2H, under solvent peak); 2.85 (m, 2H); 4.28 (t, 2H); 6.61 (d, 1H);7.21 (m, 1H); 7.30 (d, 1H); 7.95 (d, 1H).

Intermediate 24: tert-Butyl{1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

5,7-Difluoroquinolin-2(1H)-one (Intermediate 25) (500 mg, 2.8 mmol) wasdeprotonated with sodium hydride (121 mg, 60% in oil, 3.04 mmol) andalkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethylmethanesulfonate (Intermediate 6) (3.3 mmol) as described forIntermediate 20. Colorless solid, 637 mg (57%).

MS (ES): 408.30 (MH⁺) for C₂₁H₂₇F₂N₃O₃

¹H-NMR (DMSO-d₆) δ: 1.32 (m, 2H); 1.36 (s, 9H); 1.64 (m, 2H); 2.01 (t,2H); 2.48 (m, 2H); 2.88 (m, 2H); 3.18 (m, 1H); 4.28 (m, 2H); 6.61 (d,1H); 6.75 (d, 1H); 7.21 (m, 1H); 7.30 (d, 1H); 7.95 (m, 1H).

Intermediate 25: 5,7-Difluoroquinolin-2(1H)-one

The compound was prepared from(2E)-N-(3,5-difluorophenyl)-3-phenylacrylamide (Intermediate 26) (8.1 g,31.2 mmol) and aluminium trichloride (21 g, 156 mmol) in a similar wayas described for Intermediate 21. 3.47 g light brown solid (61%), mp292-318° C.

MS (ES): 181.98 (MH⁺) for C₉H₅F₂NO

¹H-NMR (DMSO-d₆) δ: 6.51 (d, 1H); 6.90 (m, 1H); 7.10 (ddd, 1H); 7.93 (d,1H); 12.05 (brs, 1H).

Intermediate 26: (2E)-N-(3,5-Difluorophenyl)-3-phenylacrylamide

The compound was prepared from 3,5-difluoroaniline (5 g, 38.7 mmol) andcinnamoylchloride (6.45 g, 38.7 mmol) in the presence of 2,6-lutidine(6.8 mL, 58 mmol) as described for Intermediate 18 to give a colorlesssolid, 8.1 g (81%).

MS (ES): 260.10 (MH⁺) for C₁₅H₁₁F₂NO

¹H-NMR (DMSO-d₆) δ: 6.76 (d, 1H); 6.92 (m, 1H); 7.35-7.49 (m, 5H);7.60-7.65 (m, 3H); 10.59 (s, 1H).

Example 96-[({1-[2-(7-Fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-fluoroquinolin-2(1H)-one(Intermediate 27) (100 mg, 0.346 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (62 mg, 0.346 mmol) and sodium triacetoxy borohydride (220mg, 1.04 mmol) were reacted as described for Example 7 to give 115 mg(74%) of the monoacetate salt of the product as a colorless solid, mp150-155° C.

MS (ES): 452.22 (MH⁺) for C₂₄H₂₆FN₅O₃

¹H-NMR (DMSO-d₆) δ: 1.22 (m, 2H); 1.75 (m, 2H); 1.89 (s, 3H); 2.01 (t,2H); 2.37 (m, 1H); 2.48 (m, 2H); 2.89 (m, 2H); 3.67 (s, 2H); 4.29 (t,2H); 4.59 (s, 2H); 6.55 (d, 1H); 7.00 (d, 1H); 7.12 (ddd, 1H); 7.28 (d,1H); 7.38 (dd, 1H); 7.78 (dd, 1H); 7.90 (d, 1H); 11.16 (brs, 1H).

Intermediate 27:1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-fluoroquinolin-2(1H)-one

The title compound was obtained from tert-butyl{1-[2-(7-fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 28) (565 mg, 1.45 mmol) by the procedure described forIntermediate 1, 425 mg (quantitative), as a colorless solid.

MS (ES): 290.19 (MH⁺) for C₁₆H₂₀FN₃O

¹H-NMR (DMSO-d₆) δ: 1.16 (m, 2H); 1.62 (m, 2H); 2.00 (t, 2H); 2.46 (m,2H, under solvent peak); 2.85 (m, 2H); 3.46 (m, 1H); 4.28 (t, 2H); 6.54(d, 1H); 7.12 (ddd, 1H); 7.36 (dd, 1H); 7.76 (dd, 1H); 7.89 (d, 1H).

Intermediate 28: tert-Butyl{1-[2-(7-fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

7-Fluoroquinolin-2(1H)-one (Intermediate 29) (500 mg, 3.06 mmol) wasdeprotonated with sodium hydride (135 mg, 60% in oil, 3.37 mmol) andalkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethylmethanesulfonate (Intermediate 6) (3.7 mmol) as described forIntermediate 20. Colorless solid, 570 mg (48%).

MS (ES): 390.21 (MH⁺) for C₂₁H₂₈FN₃O₃

¹H-NMR (DMSO-d₆) δ: 1.32 (m, 2H); 1.36 (s, 9H); 1.64 (m, 2H); 2.02 (t,2H); 2.48 (m, 2H); 2.90 (m, 2H); 3.19 (m, 1H); 4.28 (m, 2H); 6.54 (d,1H); 6.75 (d, 1H); 7.12 (m, 1H); 7.38 (m, 1H); 7.78 (dd, 1H); 7.90 (d,1H).

Intermediate 29: 7-Fluoroquinolin-2(1H)-one

The compound was prepared from(2E)-N-(3-fluorophenyl)-3-phenylacrylamide (Intermediate 30) (13.8 g,57.2 mmol) and aluminium trichloride (30.5 g, 229 mmol) in a similar wayas described for Intermediate 21 to give a mixture of the title compoundtogether with the corresponding 5-fluoro regioisomer in a ratio of 3:1.This mixture was vigorously stirred in dichloromethane (100 mL) for 3hours at room temperature and then filtered. The solid obtained wasresuspended in diethyl ether (200 mL) and stirred like above andfiltered to give 3.63 g (34%) of the crude product containing 12% of the5-fluoro regioisomer. This was used without further purification for thenext step.

MS (ES): 164.02 (MH⁺) for C₉H₆FNO

¹H-NMR (CDCl₃/MeOD) δ: 6.31 (d, 1H); 6.73 (ddd); 6.79 (dd, 1H); 7.35(dd, 1H); 7.60 (d, 1H).

Intermediate 30: (2E)-N-(3-Fluorophenyl)-3-phenylacrylamide

The compound was prepared from 3-fluoroaniline (5.8 mL, 60 mmol) andcinnamoylchloride (10 g, 60 mmol) in the presence of 2,6-lutidine (10.5mL, 90 mmol) as described for Intermediate 18 to give a colorless solid,13.9 g (96%), mp 110° C.

MS (ES): 242.20 (MH⁺) for C₁₅H₁₂FNO

¹H-NMR (DMSO-d₆) δ: 6.80 (d, 1H); 6.89 (m, 1H); 7.31-7.48 (m, 5H);7.58-7.65 (m, 3H); 7.73 (m, 1H); 10.43 (s, 1H).

Example 101-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-fluoroquinolin-2(1H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-fluoroquinolin-2(1H)-one(Intermediate 27) (100 mg, 0.346 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(57 mg, 0.346 mmol) and sodium triacetoxy borohydride (220 mg, 1.04mmol) were reacted as described for Example 7. The free base obtainedafter chromatography was dissolved in dichloromethane/ether (10 mL, 1:1)and HCl in ether (1M, 1 mL) was added under vigorous stirring. It wasevaporated to dryness under reduced pressure and the residue was takenup as a suspension in dichloromethane/hexanes (10 mL, 1:1). It wasfiltered and dried to give 118 mg (78%) of the bis HCl salt of theproduct as a colorless solid, mp >275° C. (decomposed).

MS (ES): 439.23 (MH⁺) for C₂₄H₂₇FN₄O₃

¹H-NMR (DMSO-d₆) δ: 2.10 (m, 2H); 2.37 (m, 2H); 3.10 (m, 2H); 3.20-3.38(m, 3H); 3.78 (m, 2H); 4.27 (m, 2H); 4.37 (m, 2H); 4.43 (m, 2H); 4.62(t, 2H); 6.60 (d, 1H); 7.19 (ddd, 1H); 7.41 (s, 1H); 7.78 (dd, 1H); 7.84(dd, 1H); 7.98 (d, 1H); 8.31 (s, 1H); 9.91 (brs, 2H); 11.04 (brs, 1H).

Example 116-[({1-[2-(7-Methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxy-3,4-dihydroquinolin-2(1H)-one(Intermediate 31) (110 mg, 0.36 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (65 mg, 0.325 mmol) and sodium triacetoxy borohydride (220mg, 1.04 mmol) were reacted as described for Example 1, but the aqueousworkup was omitted. Chromatography on a Phenomenex Synergy Polar-RP4 μmcolumn, eluent: 30-60% acetonitrile, 10 mM ammonium acetate pH8,followed by chromatography on silica gel with dichloromethane/methanol(7:1). The bis HCl salt of the product was prepared as described forExample 10 to give 46 mg (24%) as a colorless solid, mp >285° C. (dec).

MS (ES): 466.21 (MH⁺) for C₂₅H₃₁N₅O₄

¹H-NMR (DMSO-d₆) δ: 2.10 (m, 2H); 2.36 (m, 2H); 2.53 (t, 2H); 2.86 (t,2H); 3.10 (m, 2H); 3.16 (m, 2H); 3.36 (m, 1H); 3.70 (m, 2H); 3.73 (s,3H); 4.16 (m, 2H); 4.28 (m, 2H); 4.70 (s, 2H); 6.80 (m, 1H); 6.86 (s,1H); 7.23-7.28 (m, 2H); 7.45 (d, 1H); 9.70 (brs, 2H); 11.07 (brs, 1H);11.37 (s, 1H).

Intermediate 31:1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxy-3,4-dihydroquinolin-2(1H)-one

The title compound was obtained from tert-butyl{1-[2-(7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 32) (550 mg, 1.36 mmol) by the procedure described forIntermediate 1, 338 mg (82%), as a colorless oil.

MS (ES): 304.23 (MH⁺) for C₁₇H₂₅N₃O₄

¹H-NMR (DMSO-d₆) δ: 1.19 (m, 2H); 1.62 (m, 2H); 1.96 (t, 2H); 2.36 (t,2H); 2.46 (m, 2H); 2.73-2.80 (m, 5H); 3.71 (s, 3H); 3.91 (m, 2H);6.77-6.84 (m, 2H); 7.04 (m, 1H).

Intermediate 32: tert-Butyl{1-[2-(7-methoxy-2-oxo-3,4-dihydroquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

7-Methoxy-3,4-dihydroquinolin-2(1H)-one (Intermediate 33) (300 mg, 1.78mmol) was deprotonated with sodium hydride (75 mg, 60% in oil, 1.86mmol) and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (2.03 mmol) as described for Intermediate 2.Chromatography on silica gel eluting with ethyl acetate and thenacetone/dichloromethane (4:1) gave the product as a colorless oil, 559mg (82%).

MS (ES): 404.21 (MH⁺) for C₂₂H₃₃N₃O₄

¹H-NMR (DMSO-d₆) δ: 1.32 (m, 2H); 1.36 (s, 9H); 1.64 (m, 2H); 1.93-2.00(m, 4H); 2.37 (m, 2H); 2.47 (m, 2H); 2.78 (m, 2H); 3.16 (m, 1H); 3.71(s, 3H); 3.91 (t, 2H); 6.72-6.82 (m, 3H); 7.05 (d, 1H).

Intermediate 33: 7-Methoxy-3,4-dihydroquinolin-2(1H)-one

A mixture of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (3.0 g, 17 mmol)and triethyl amine (3.14 mL, 22 mmol) indichloromethane/methanol/acetonitrile (10:1:10, 168 mL) was treated with(trimethylsilyl)diazomethane (2M solution in hexanes, 10.25 mL, 20.5mmol). It was stirred over night at room temperature, the solvent wasremoved under reduced pressure and chromatography on silica gel withhexanes/acetone (1:1) gave 2.2 g (67%) of the product as a colorlesssolid.

MS (ES): 178.16 (MH⁺) for C₁₀H₁₁NO₂

¹H-NMR (DMSO-d₆) δ: 2.38 (t, 2H); 2.81 (t, 2H); 3.68 (s, 3H); 6.68-6.78(m, 3H); 9.90 (brs, 1H).

Example 12(3S,4R)-1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylicacid

A solution of methyl(3S,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate(Example 13) (120 mg, 0.233 mmol) in tetrahydrofuran/water (1:1, 10 mL)was treated with sodium hydroxide (15% aqueous, 0.2 mL) at roomtemperature for 3 hours. It was quenched with glacial acetic acid (1 mL)and concentrated to dryness under reduced pressure. Chromatography on aC18 cartridge (RediSep, ISCO) with 0-25% acetonitrile in water,containing 0.1% acetic acid and treatment with HCl as described forExample 10 gave 113 mg (90%) of the mono hydrochloride salt of theproduct as a colorless solid, mp 100-180° C.

MS (ES): 501.03 (MH⁺) for C₂₅H₂₆F₂N₄O₅

¹H-NMR (DMSO-d₆) δ: 2.02 (m, 2H); 2.60 (m, 2H); 3.15-3.51 (m, 8H); 4.18(m, 2H); 4.33 (m, 2H); 4.37 (m, 2H); 4.50 (m, 1H); 6.62 (d, 1H); 7.12(s, 1H); 7.24 (m, 1H); 7.41 (m, 1H); 7.98 (d, 1H); 8.15 (s, 1H).

Example 13(3S,4R)-1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidine-3-carboxylicacid

Methyl(3S,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidine-3-carboxylate(Example 15) (80 mg, 0.155 mmol) was treated with sodium hydroxide asdescribed for Example 12 to give 51 mg (61%) of the mono hydrochloridesalt of the product as a colorless solid, mp 150-180° C.

MS (ES): 504.19 (MH⁺) for C₂₆H₂₅F₄N₃O₃

¹H-NMR (DMSO-d₆) δ: 2.10 (m, 2H); 2.75-3.75 (m, 8H); 3.86 (m, 2H); 4.33(m, 1H); 4.54 (m, 1H); 6.50 (m, 1H); 6.64 (d, 1H); 6.91 (d, 1H);7.19-7.34 (m, 3H); 7.48 (m, 2H); 8.00 (s, 1H); 9.19 (brs, 1H).

Example 14 Methyl(3S,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate

Methyl(3S,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate(Intermediate 34) (120 mg, 0.328 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(54 mg, 0.328 mmol) and sodium triacetoxy borohydride (209 mg, 0.98mmol) were reacted as described for Example 6. Chromatography on silicagel with dichloromethane/methanol (20:1) gave 130 mg (77%) of product asa colorless hard foam.

MS (ES): 515.03 (MH⁺) for C₂₆H₂₈F₂N₄O₅

¹H-NMR (DMSO-d₆) δ: 1.52 (m, 1H); 1.75 (m, 1H); 2.43 (m, 1H); 2.50 (m,1H); 2.54 (m, 2H); 2.60-2.73 (m, 3H); 2.87 (m, 1H); 3.51 (s, 3H); 3.53(d, 1H); 3.69 (d, 1H); 4.22-4.34 (m, 6H); 6.61 (d, 1H); 6.86 (s, 1H);7.21 (m, 1H); 7.30 (m, 1H); 7.95 (d, 1H).

Example 15 Methyl(3S,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidine-3-carboxylate

Methyl(3S,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate(Intermediate 34) (120 mg, 0.328 mmol),(2E)-3-(2,5-difluorophenyl)acrylaldehyde (FR 2872164) (54 mg, 0.328mmol) and sodium triacetoxy borohydride (209 mg, 0.98 mmol) were reactedas described for Example 6. Chromatography on silica gel withdichloromethane/N,N-dimethylformamide (30:1) gave 83 mg (49%) of productas a colorless hard foam.

MS (ES): 518.10 (MH⁺) for C₂₇H₂₇F₄N₃O₃

¹H-NMR (DMSO-d₆) δ: 1.56 (m, 1H); 1.75 (m, 1H); 1.90 (m, 1H); 2.41 (m,1H); 2.51-2.72 (m, 5H); 2.90 (m, 1H); 3.25 (dd, 1H); 3.39 (dd, 1H); 3.51(s, 3H); 4.29 (m, 2H); 6.42 (m, 1H); 6.57 (d, 1H); 6.61 (d, 1H); 7.09(m, 1H); 7.17-7.24 (m, 2H); 7.30 (m, 7.43 (m, 1H); 7.95 (d, 1H).

Intermediate 34: Methyl(3S,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate

A solution of methyl(3S,4R)-4-{[(benzyloxy)carbonyl]amino}-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate(Intermediate 35) (595 mg, 1.19 mmol) in methanol (10 mL) washydrogenated over palladium on carbon (10%, wet) at normal pressure androom temperature for 30 minutes. It was filtered through a 0.45 μmmembrane, washed with methanol and the wash and filtrate wereconcentrated under reduced pressure to give 395 mg (91%) of the productas a colorless hard foam.

MS (ES): 365.98 (MH⁺) for C₁₈H₂₁F₂N₃O₃

¹H-NMR (DMSO-d₆) δ: 1.58 (m, 2H); 2.37-2.69 (m, 7H); 3.14 (m, 1H); 3.53(s, 3H); 4.28 (m, 2H); 6.60 (d, 1H); 7.21 (m, 1H); 7.30 (m, 1H); 7.95(d, 1H).

Intermediate 35: Methyl(3S,4R)-4-{[(benzyloxy)carbonyl]amino}-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate

5,7-Difluoroquinolin-2(1H)-one (Intermediate 25) (350 mg, 1.93 mmol) wasdeprotonated with sodium hydride (85 mg, 60% in oil, 2.13 mmol) andalkylated with methyl(3S,4R)-4-{[(benzyloxy)carbonyl]amino}-1-(2-chloroethyl)piperidine-3-carboxylate(Intermediate 36) (1.93 mmol) as described for Intermediate 20.Colorless hard foam, 604 mg (63%).

MS (ES): 500.05 (MH⁺) for C₂₆H₂₇F₂N₃O₅

¹H-NMR (60° C.) (DMSO-d₆) δ: 1.64 (m, 1H); 1.72 (m, 1H); 2.44 (m, 1H);2.59 (t, 2H); 2.61-2.76 (m, 3H); 2.85 (dd, 1H); 3.49 (s, 3H); 3.93 (m,1H); 4.28 (m, 2H); 4.99 (d, 1H); 5.03 (d, 1H); 6.60 (d, 1H); 6.90 (m,1H); 7.13 (m, 1H); 7.24-7.37 (m, 6H); 7.93 (d, 1H).

Intermediate 36: Methyl (3S,4R)-4-{[(benzyloxy)carbonyl]amino}-1-(2-chloroethyl)piperidine-3-carboxylate

Methyl(3S,4R)-4-{[(benzyloxy)carbonyl]amino}-1-(2-hydroxyethyl)piperidine-3-carboxylate(Intermediate 37) (650 mg, 1.93 mmol) was reacted with methanesulfonylchloride (0.18 mL, 2.32 mmol) in the presence of triethylamine (0.38 mL,2.7 mmol) as described for Intermediate 6. The crude chloride was usedwithout delay for the next step.

MS (ES): 355/357 (MH⁺) for C₁₇H₂₃N₂O₄

Intermediate 37: Methyl(3S,4R)-4-{[(benzyloxy)carbonyl]amino}-1-(2-hydroxyethyl)piperidine-3-carboxylate

A mixture of methyl(3S,4R)-4-{[(benzyloxy)carbonyl]amino}piperidine-3-carboxylate (WO2005/066176) (2.29 g, 7.83 mmol), N,N-diisopropylethylamine (2.05 mL,11.75 mmol and 2-bromoethanol (0.722 mL, 10.18 mmol) in dry acetonitrile(17 mL) was heated in the microwave at 70° C. for 4.5 hours. The solventwas removed under reduced pressure and the residue taken up in ethylacetate (200 mL) and washed with saturated aqueous sodiumhydrogencarbonate solution (100 mL). The aqueous phase was backextracted once with ethyl acetate (100 mL) and the combined organicphases were dried over sodium sulfate. Chromatography on silica gel withdichloromethane/methanol (12:1) gave 2.0 g (76%), mp 73° C.

MS (ES): 337.16 (MH⁺) for C₁₇H₂₄N₂O₅

¹H-NMR (DMSO-d₆) δ: 1.66 (m, 2H); 2.34-2.55 (m, 5H); 2.67-2.79 (m, 2H);3.44 (dt, 2H); 3.51 (s, 3H); 3.95 (m, 1H); 4.31 (t, 1H); 4.97 (d, 1H);5.02 (d, 1H); 7.21 (d, 1H); 7.25-7.38 (m, 5H).

Example 16(3R,4R)-1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylicacid

Methyl(3R,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate(Example 18) (201 mg, 0.4 mmol) was saponified and converted into thebis hydrochloride salt as described for Example 12, 194 mg (87%),colorless solid, mp >190° C.

MS (ES): 501.22 (MH⁺) for C₂₅H₂₆F₂N₄O₅

¹H-NMR (DMSO-d₆) δ: 2.24 (m, 1H); 2.46 (m, 1H); 3.12 (m, 1H); 3.34 (m,4H); 3.58 (m, 1H); 3.83 (m, 1H); 3.93 (m, 1H); 4.24 (d, 1H); 4.31-4.44(m, 5H); 4.63 (m, 2H); 6.66 (d, 1H); 7.26-7.31 (m, 2H); 7.69 (d, 1H);8.02 (d, 1H); 8.25 (s, 1H); 11.51 (bs, 1H).

Example 17(3R,4R)-1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidine-3-carboxylicacid

Methyl(3R,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidine-3-carboxylate(Example 19) (106 mg, 0.2 mmol) was treated with sodium hydroxide asdescribed for Example 12 to give 82 mg (69%) of the bis hydrochloridesalt of the product as a colorless solid, mp >205° C.

MS (ES): 504.23 (MH⁺) for C₂₆H₂₅F₄N₃O₃

¹H-NMR (DMSO-d₆) δ: 2.15 (m, 1H); 2.40 (m, 1H); 3.01-3.98 (m, 10H); 4.60(m, 2H); 6.50 (m, 1H); 6.67 (d, 1H); 6.95 (d, 1H); 7.20-7.35 (m, 3H);7.47 (m, 1H); 7.62 (m, 1H); 8.02 (d, 1H).

Example 18 Methyl(3R,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidine-3-carboxylate

Methyl(3R,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate(Intermediate 38) (195 mg, 0.53 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(88 mg, 0.53 mmol) and sodium triacetoxy borohydride (339 mg, 1.6 mmol)were reacted as described for Example 14 to give 216 mg (79%) of productas a colorless hard foam.

MS (ES): 515.23 (MH⁺) for C₂₆H₂₈F₂N₄O₅

¹H-NMR (DMSO-d₆) δ: 1.18 (m, 1H); 1.92 (m, 1H); 2.05 (ddd, 1H); 2.14(dd, 1H); 2.34 (ddd, 1H); 2.52 (t, 2H); 2.57 (m, 1H); 2.88 (m, 1H); 3.03(m, 1H); 3.57 (d, 1H); 3.58 (s, 3H); 3.69 (d, 1H); 4.24-4.33 (m, 6H);6.61 (d, 1H); 6.87 (s, 1H); 7.21 (ddd, 1H); 7.33 (m, 1H); 7.93-7.96 (m,2H).

Example 19 Methyl(3R,4R)-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidine-3-carboxylate

Methyl(3R,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate(Intermediate 38) (195 mg, 0.53 mmol),(2E)-3-(2,5-difluorophenyl)acrylaldehyde (FR 2872164) (90 mg, 0.53 mmol)and sodium triacetoxy borohydride (339 mg, 1.6 mmol) were reacted asdescribed for Example 6. Chromatography on silica gel withdichloromethane/N,N-dimethylformamide (25:1 to 15:1) gave 119 mg (43%)of product as a colorless oil.

MS (ES): 518.25 (MH⁺) for C₂₇H₂₇F₄N₃O₃

¹H-NMR (DMSO-d₆) δ: 1.20 (m, 1H); 1.94 (m, 1H); 2.08 (ddd, 1H); 2.16(dd, 1H); 2.34 (ddd, 1H); 2.53 (t, 2H); 2.61 (ddd, 1H); 2.90 (m, 1H);3.04 (m, 1H); 3.24 (dd, 1H); 3.39 (dd, 1H); 3.58 (s, 3H); 4.28 (m, 2H);6.40 (m, 1H); 6.55-6.62 (m, 2H); 7.05-7.25 (m, 3H); 7.32 (d, 1H); 7.42(m, 1H); 7.95 (d, 1H).

Intermediate 38: Methyl(3R,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate

Methyl(3R,4R)-4-{[(benzyloxy)carbonyl]amino}-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate(Intermediate 39) (535 mg, 1.07 mmol) was hydrogenated as described forIntermediate 34 to give 391 mg (quantitative) of the product as acolorless hard foam.

MS (ES): 366 (MH⁺) for C₁₈H₂₁F₂N₃O₃

Intermediate 39: Methyl(3R,4R)-4-{[(benzyloxy)carbonyl]amino}-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate

5,7-Difluoroquinolin-2(1H)-one (Intermediate 25) (350 mg, 1.93 mmol) wasdeprotonated with sodium hydride (85 mg, 60% in oil, 2.13 mmol) andalkylated with methyl(3R,4R)-4-{[(benzyloxy)carbonyl]amino}-1-{2-[(methylsulfonyl)oxy]ethyl}piperidine-3-carboxylate(Intermediate 40) (1.93 mmol) as described for Intermediate 20 to givethe product as a colorless hard foam, 538 mg (56%).

MS (ES): 500.38 (MH⁺) for C₂₆H₂₇F₂N₃O₅

¹H NMR (60° C.) (DMSO-d₆) δ: 1.40 (dddd, 1H); 1.70 (m, 1H); 2.10-1.45(m, 2H); 2.44 (ddd, 1H); 2.54 (t, 2H); 2.89 (m, 1H); 3.07 (m, 1H); 3.49(s, 3H); 3.54 (m, 1H); 4.28 (m, 2H); 4.95 (d, 1H); 4.99 (d, 1H); 6.61(d, 1H); 7.21 (ddd, 1H); 7.29-7.37 (m, 7H); 7.95 (d, 1H).

Intermediate 40: Methyl(3R,4R)-4-{[(benzyloxy)carbonyl]amino}-1-{2-[(methylsulfonyl)oxy]ethyl}piperidine-3-carboxylate

Methyl(3R,4R)-4-{[(benzyloxy)carbonyl]amino}-1-(2-hydroxyethyl)piperidine-3-carboxylate(Intermediate 41) (650 mg, 1.93 mmol) was reacted with methanesulfonylchloride (0.18 mL, 2.32 mmol) in the presence of triethylamine (0.38 mL,2.7 mmol) as described for Intermediate 6. The crude product was usedwithout delay for the next step.

MS (ES): 415.3 (MH⁺ for C₁₈H₂₆N₂O₇S

Intermediate 41: Methyl(3R,4R)-4-{[(benzyloxy)carbonyl]amino}-1-(2-hydroxyethyl)piperidine-3-carboxylate

Methyl (3S,4R)-4-{[(benzyloxy)carbonyl]amino}piperidine-3-carboxylate(WO 2005/066176) (2.0 g, 6.84 mmol), N,N-diisopropylethylamine (1.8 mL,10.26 mmol) and 2-bromoethanol (0.63 mL, 8.9 mmol) were reacted asdescribed for Intermediate 37 to give 1.38 g (60%) of the product as acolorless oil.

MS (ES): 337.36 (MH⁺) for C₁₇H₂₄N₂O₅

¹H-NMR (DMSO-d₆) δ: 1.43 (dddd, 1H); 1.70 (m, 1H); 1.97-2.14 (m, 2H);2.37 (t, 2H); 2.49 (m, 1H); 2.80 (m, 1H); 2.94 (m, 1H); 3.44 (dt, 2H);3.50 (s, 3H); 3.54 (m, 1H); 4.39 (t, 1H); 4.95 (d, 1H); 5.00 (d, 1H);7.27-7.38 (m, 6H).

Example 20Cis(±)6-[({1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-3-hydroxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

Cis(±)1-{2-[4-amino-3-hydroxypiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one(175 mg, 0.54 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (96 mg, 0.54 mmol) and sodium triacetoxy borohydride (344mg, 1.6 mmol) were reacted as described for Example 1 to give 186 mg(71%) of the free base of the product as a colorless oil.

MS (ES): 486.24 (MH⁺) for C₂₄H₂₅F₂N₅O₅ ¹H-NMR (MeOD) δ: 1.67-1.78 (m,2H); 2.22 (m, 1H); 2.33 (d, 1H); 2.55-2.69 (m, 3H); 2.90 (m, 1H); 3.06(m, 1H); 3.75 (d, 1H); 3.79 (d, 1H); 3.91 (m, 1H); 4.30-4.46 (m, 2H);4.59 (s, 2H); 6.61 (d, 1H); 6.93 (ddd, 1H); 6.95 (d, 1H); 7.21 (d, 1H);7.27 (m, 1H); 7.96 (d, 1H).

Intermediate 42:Cis(±)1-{2-[4-amino-3-hydroxypiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one

Cis(±)1-{2-[4-azido-3-hydroxypiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one(Intermediate 43) (190 mg, 0.54 mmol) was hydrogenated as described forIntermediate 34, for 3 hours, to give the product as a colorless oil,175 mg (quantitative).

MS (ES): 324.02 (MH⁺) for C₁₆H₁₉F₂N₃O₂

¹H-NMR (CDCl₃) δ: 1.82 (m, 2H); 2.25 (ddd, 1H); 2.39 (d, 1H); 2.62-2.73(m, 3H); 2.90 (m, 1H); 2.98 (m, 1H); 3.13 (m, 1H); 3.92 (m, 1H); 4.23(ddd, 1H); 4.44 (ddd, 1H); 6.63 (d, 1H); 6.70 (ddd, 1H); 6.91 (d, 1H);7.85 (d, 1H).

Intermediate 43:Cis(±)1-{2-[4-azido-3-hydroxypiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one

5,7-Difluoroquinolin-2(1H)-one (Intermediate 25) (389 mg, 2.15 mmol) wasdeprotonated with sodium hydride (95 mg, 60% in oil, 2.36 mmol) andalkylated with cis(±) 2-(4-azido-3-hydroxypiperidin-1-yl)ethylmethanesulfonate (Intermediate 44) (2.15 mmol) as described forIntermediate 20, except after 24 hours, potassium carbonate (100 mg,0.72 mmol) was added and the resulting mixture was stirred for another24 hours at room temperature to give the product as a colorless hardfoam, 195 mg (26%).

MS (ES): 350.15 (MH⁺) for C₁₆H₁₇F₂N₅O₂

¹H-NMR (DMSO-d₆) δ: 1.56 (m, 1H); 1.71 (m, 1H); 2.32 (m, 1H); 2.40 (m,1H); 2.48 (m, 1H); 2.53 (dd, 2H); 2.59 (m, 1H); 3.61-3.71 (m, 2H); 4.29(dd, 2H); 5.05 (d, 1H); 6.61 (d, 1H); 7.21 (ddd, 1H); 7.32 (d, 1H); 7.95(d, 1H).

Intermediate 44: Cis(±) 2-(4-azido-3-hydroxypiperidin-1-yl)ethylmethanesulfonate

A solution of cis(±)4-azido-1-(2-hydroxyethyl)piperidin-3-ol(Intermediate 45) (0.4 g, 2.15 mmol) in dry dichloromethane (15 mL) and2,6-lutidine (0.325 mL, 2.8 mmol) was treated at −20° C. dropwise with asolution of methanesulfonyl chloride (0.175 mL, 2.26 mmol) indichloromethane (5 mL). The temperature was allowed to reach 0° C. andkept at 0° C. for 10 hours. The resulting reaction mixture was dilutedwith dichloromethane (50 mL) and washed with saturated aqueous sodiumhydrogen carbonate solution (10 mL). The aqueous phase was backextracted with dichloromethane (20 mL) and the combined organic phaseswere dried over sodium sulfate. The solvent was removed under reducedpressure, and the residue was codistilled with city DMF (10 mL) withoutbeating. This crude preparation of the mesylate was used without furtherpurification directly for the next step.

MS (ES): 265.02 (MH⁺) for C₈H₁₆N₄O₄S

Intermediate 45: Cis(±)4-azido-1-(2-hydroxyethyl)piperidin-3-ol

Cis(±)4-azidopiperidin-3-ol (prepared following the procedure describedin WO 2005/066176 for the chiral material) (0.945 g, 6.65 mmol),N,N-diisopropylethylamine (1.7 mL, 10 mmol) and 2-bromoethanol (0.61 mL,8.64 mmol) were reacted as described for Intermediate 37, except heatingfor one hour. The solvent was removed under reduced pressure. Theresidue was taken up in dichloromethane (100 mL), washed with 1M sodiumhydroxide solution (30 mL) and the aqueous phase was back extracted fivetimes with dichloromethane (5×100 mL). The combined organic phases weredried over sodium sulfate. Chromatography on silica gel withdichloromethane/methanol 3:1 gave 1.15 g (93%) of the product as acolorless oil.

MS (ES): 187.24 (MH⁴) for C₇H₁₄N₄O₂

¹H-NMR (DMSO-d₆) δ: 1.61 (m, 1H); 1.72 (m, 1H); 2.28-2.38 (m, 5H); 2.45(m, 1H); 3.43 (ddd, 2H); 3.57 (m, 1H); 3.73 (m, 1H); 4.33 (dd, 1H); 5.01(d, 1H).

Example 214-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one

A mixture of4-[2-(4-aminopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-onetrifluoroacetate (Intermediate 46) (0.4 mmol), N,N-diisopropylethylamine(1 mL) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO2004/058144) (74 mg, 0.45 mmol) in dichloroethane/methanol (1:1, 10 mL)was reacted and reduced with sodium cyanoborohydride (50 mg, 0.74 mmol)as described for Example 4. Reverse phase chromatography withwater/acetonitrile/trifluoroacetic acid gave the product as thetrifluoroacetic acid salt. The salt was dissolved in water andchloroform and basified with saturated sodium carbonate. The layers wereseparated and the aqueous was extracted with chloroform. The organicextracts were dried over magnesium sulfate and evaporated to dryness togive the free base of the title compound as a gum, 54 mg (32%).

MS (ES): 455.33 (MH⁺) for C₂₄H₃₀N₄O₅

¹H-NMR (CDCl₂) δ: 1.46 (m, 213); 1.88 (m, 2H); 2.14 (m, 2H); 2.54 (m,1H); 2.58 (t, J=7.3 Hz, 2H); 2.95 (m, 2H); 3.78 (s, 3H); 3.79 (s, 2H);4.01 (t, J=7.4 Hz, 2H); 4.29 (m, 4H); 4.52 (s, 2H); 6.50 (dd, J=6.2, 2.7Hz, 1H); 6.67 (d, J=2.7 Hz, 1H); 6.81 (s, 1H); 6.89 (d, J=8.7 Hz, 1H);8.08 (s, 1H).

Intermediate 46:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzoxazin 3(4H)-one

tert-Butyl{1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-4-yl}carbamate(Intermediate 47) (510 mg, 1.26 mmol) was reacted as described forIntermediate 14. The crude trifluoro acetate of the title compound wasused without further purification for the next step (quantitativeyield).

MS (ES): 306 (MH⁺) for C₁₅H₂₂N₄O₃

Intermediate 47: tert-Butyl{1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-4-yl}carbamate

6-Methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 48) (380 mg, 2.1mmol) was deprotonated with sodium hydride (100 mg, 60% in oil, 2.5mmol) and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (2.3 mmol) as described for Intermediate 2.Chromatography on silica gel with hexanes/ethyl acetate (1:1) afforded510 mg (60%) of the product.

MS (ES): 406.49 (MH⁺) for C₂₁H₃₁N₃O₅

¹H-NMR (CDCl₃-d) δ: 1.34 (m, 2H); 1.36 (m, 2H); 1.62 (m, 2H); 1.98 (m,2H); 2.43 (m, 2H); 2.84 (m, 2H); 3.20 (m, 1H); 3.73 (s, 3H); 3.96 (m,2H); 4.53 (s, 2H); 6.56 (m, 1H); 6.76 (m, 1H); 6.92 (m, 1H).

Intermediate 48: 6-Methoxy-2H-1,4-benzoxazin-3(4H)-one

To a solution of ethyl (4-methoxy-2-nitrophenoxy)acetate (Intermediate49) (1.8 g, 7.1 mmol) in acetic acid (20 mL) was added iron powder (1.1g, 19.9 mmol). The reaction was heated at 90° C. for 3 hours. It wascooled to room temperature, diluted with ethyl acetate, filtered throughcelite, and concentrated to dryness under reduced pressure. Silica gelchromatography with hexanes/ethyl acetate (7:3) afforded product, 1 g(79%).

MS (ES): 180.15 (MH⁺) for C₉H₉NO₃

¹H-NMR (CDCl₃-d) δ: 3.75 (s, 3H); 4.55 (s, 2H); 6.40 (d, 1H); 6.50 (dd,1H); 6.89 (d, 1H); 8.85 (bs, 1H).

Intermediate 49: Ethyl (4-methoxy-2-nitrophenoxy)acetate

A mixture of 4-methoxy-2-nitrophenol (2 g, 11.8 mmol), cesium carbonate(7.7 g, 23.6 mmol) and 2-bromo ethyl acetate (1.31 mL, 11.8 mmol) inacetone (50 mL) was heated at 50° C. overnight. The mixture was heatedat 55° C. for an additional 1 hour, then filtered and concentrated todryness under reduced pressure. Silica gel chromatography withhexanes/ethyl acetate (4:1) afforded product, 1.8 g (60%).

MS (ES): 256.26 (MH⁺) for C₁₁H₁₃NO₆

¹H-NMR (CDCl₃-d) δ: 1.28 (t, 3H); 3.81 (s, 3H); 4.25 (q, 2H); 4.70 (s,2H); 7.04 (m, 2H); 7.39 (d, 1H).

Example 226-[({1-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-aminopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-onetrifluoroacetate (Intermediate 46) (0.4 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (80 mg, 0.44 mmol) and sodium cyanoborohydride were reactedas described under Example 21, but, the reaction was stirred at roomtemperature overnight after sodium cyanoborohydride addition to give thetitle compound as a free base, 30 mg (17%).

MS (ES): 468.27 (MH⁺) for C₂₄H₂₉N₅O₅

¹H-NMR (CDCl₃-d) δ: 1.56 (m, 2H); 1.96 (m, 2H); 2.18 (m, 3H); 2.62 (m,3H); 3.01 (m, 2H); 3.79 (s, 3H); 3.84 (s, 2H); 4.06 (m, 2H); 4.51 (s,2H); 4.63 (s, 2H); 6.51 (1H); 6.67 (s, 1H); 6.89 (1H); 6.95 (1H); 7.20(1H).

Example 236-[({1-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzothiazin-3(4H)-one(Intermediate 50) (0.9 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (190 mg, 1.1 mmol) and sodium cyanoborohydride (110 mg,1.77 mmol) were reacted as described under Example 21, with stirring for2.5 hours at room temperature after sodium cyanoborohydride addition.The title compound was obtained as a solid, 52 mg (12%).

MS (ES): 484.26 (MH⁺) for C₂₄H₂₉N₅O₄S

¹H-NMR (CDCl₃-d) δ: 1.49 (m, 2H); 1.91 (m, 3H); 2.16 (m, 2H); 2.54 (m,1H); 2.61 (m, 2H); 2.96 (m, 2H); 3.33 (s, 2H); 3.81 (s, 5H); 4.09 (m,2H); 4.63 (s, 2H); 6.58 (dd, 1H); 6.87 (d, 1H); 6.93 (d, 1H); 7.20 (d,1H); 7.24 (d, 1H).

Intermediate 50:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzothiazin-3(4H)-one

tert-Butyl{1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 51) (750 mg, 1.78 mmol) was reacted as described forIntermediate 14. The crude trifluoro acetate of the title compound wasused without further purification for the next step (quantitativeyield).

MS (ES): 322 (MH⁺) for C₁₆H₂₃N₃O₂S

Intermediate 51: tert-Butyl{1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl)ethyl]piperidin-4-yl}carbamate

6-Methoxy-2H-1,4-benzothiazin-3(4H)-one (Intermediate 52) (410 mg, 2.1mmol) was deprotonated with sodium hydride (100 mg, 60% in oil, 2.5mmol) and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (2.3 mmol) as described for Intermediate 2.Chromatography on silica gel with hexanes/ethyl acetate (1:3) afforded750 mg (85%) of the product.

MS (ES): 422.24 (MH⁺) for C₂₁H₃₁N₃O₄S

¹H-NMR (CDCl₃-d): δ: 1.40 (m, 2H); 1.45 (s, 9H); 1.92 (m, 2H); 2.22 (m,2H); 2.62 (t, 2H); 2.88 (m, 2H); 3.35 (s, 2H); 3.49 (m, 1H); 3.82 (s,3H); 4.08 (t, 2H); 4.43 (m, 1H); 6.61 (dd, 1H); 6.86 (d, 1H); 7.28 (s,1H).

Intermediate 52: 6-Methoxy-2H-1,4-benzothiazin-3(4H)-one

Prepared from ethyl [(4-methoxy-2-nitrophenyl)thio]acetate (Intermediate53, 3 g, 11 mmol) according to procedure described for preparation ofIntermediate 48. Silica gel chromatography with hexanes/ethyl acetate(3:2) afforded desired product, 2 g (93%).

MS (ES): 196.12 (MH⁺) for C₉H₉NO₂S

¹H-NMR (CDCl₃-d) δ: 3.39 (s, 2H); 3.78 (s, 3H); 6.44 (d, 1H); 6.59 (dd,1H); 7.20 (d, 1H); 8.63 (bs, 1H).

Intermediate 53: Ethyl [(4-methoxy-2-nitrophenyl)thio]acetate

Ethyl mercaptoacetate (2.3 mL, 21.5 mmol) was dissolved in DMF (20 mL)and cooled to 0° C. Sodium hydride (1 g, 60% in oil, 25.8 mmol) wasadded and the reaction was stirred for 1 hour. Then a solution of1-bromo-4-methoxy-2-nitrobenzene (5 g, 21.5 mmol) in DMF (20 mL) wasadded at 0° C. The reaction mixture was allowed to warm to roomtemperature and stirred overnight. It was diluted with ethyl acetate,washed with water (four times) and with brine and then dried overmagnesium sulfate. Silica gel chromatography with hexanes/ethyl acetate(4:1) afforded the product, 3 g (52%).

MS (ES): 272.14 (MH⁺) for C₁₁H₁₃NO₅S

¹H-NMR (CDCl₃-d) δ: 1.24 (t, 3H); 3.68 (s, 2H); 3.86 (s, 3H); 4.18 (q,2H); 7.15 (dd, 1H); 7.47 (d, 1H); 7.65 (d, 1H).

Example 244-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methoxy-2H-1,4-benzothiazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzothiazin-3(4H)-one(Intermediate 50) (0.9 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(180 mg, 1.1 mmol), and sodium cyanoborohydride (110 mg, 1.76 mmol) werereacted as described under Example 21 to give 55 mg (13%) product as adry film.

MS (ES): 471.26 (MH⁺) for C_(24l H) ₃₀N₄O₄S

¹H-NMR (CDCl₃-d) δ: 1.47 (m, 2H); 1.91 (m, 2H); 2.15 (m, 2H); 2.54 (m,1H); 2.60 (t, J=6.4 Hz, 2H); 2.94 (m, 2H); 3.33 (s, 2H); 3.47 (s, 2H);3.80 (s, 5H); 4.08 (t, 2H); 4.29 (m, 4H); 6.58 (dd, 1H); 6.80 (s, 1H);6.88 (d, 1H); 7.23 (d, 1H); 8.08 (s, 1H).

Example 256-[({1-[2-(6-Fluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-fluoro-2H-1,4-benzoxazin-3(4H)-one(Intermediate 54), (0.7 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (150 mg, 0.84 mmol) and sodium cyanoborohydride (90 mg, 1.4mmol) were reacted as described under Example 21 to give 51 mg (16%)product as a solid.

MS (ES): 456.24 (MH⁺) for C₂₃H₂₆FN₅O₄

¹H-NMR (CDCl₃-d) δ: 1.52 (m, 2H); 1.94 (m, 2H); 2.15 (m, 2H); 2.57 (m,1H); 2.59 (t, J=7.1 Hz, 2H); 2.97 (m, 2H); 3.84 (s, 2H); 4.01 (t, J=7.1Hz, 2H); 4.54 (s, 2H); 4.62 (s, 2H); 6.68 (m, 1H); 6.86 (m, 1H); 6.89(m, 1H); 6.95 (d, J=8.1 Hz, 1H); 7.20 (d, J=8.1 Hz, 1H).

Intermediate 54:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-fluoro-2H-1,4-benzoxazin-3(4H)-one

tert-Butyl{1-[2-(6-fluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 55) (640 mg, 1.56 mmol) was reacted as described forIntermediate 14. The crude trifluoro acetate of the title compound wasused without further purification for the next step (quantitativeyield).

MS (ES): 294 (MH⁺) for C₁₅H₂₀FN₃O₂

Intermediate 55: tert-Butyl{1-[2-(6-fluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate

Commercially available 6-fluoro-2H-1,4-benzoxazin-3(4H)-one (350 mg, 2.1mmol) was deprotonated with sodium hydride and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (2.3 mmol) as described for Intermediate 2.Chromatography on silica gel with hexanes/ethyl acetate (1:1) gave 550mg (67%) product.

MS (ES): 394.26 (MH⁺) for C₂₀H₂₈FN₃O₄

¹H-NMR (CDCl₃-d) δ: 1.39 (m, 2H); 1.43 (s, 9H); 1.92 (m, 2H); 2.20 (m,2H); 2.58 (t, 2H); 2.88 (m, 2H); 3.45 (m, 1H); 3.98 (t, 2H); 4.41 (m,1H); 4.55 (s, 2H); 6.68 (m, 1H); 6.85 (m, 1H); 6.91 (m, 1H).

Example 264-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-fluoro-2H-1,4-benzoxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-fluoro-2H-1,4-benzoxazin-3(4H)-one(Intermediate 54) (0.7 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(140 mg, 0.84 mmol), and sodium cyanoborohydride (90 mg, 1.4 mmol) werereacted as described under Example 21 to give 100 mg (32%) product.

MS (ES): 443.24 (MH⁺) for C₂₃H₂₇FN₄O₄

¹H-NMR (CDCl₃-d) δ: 1.46 (m, 2H); 1.90 (m, 2H); 2.13 (m, 2H); 2.53 (m,1H); 2.57 (t, 2H); 2.93 (m, 2H); 3.80 (s, 2H); 3.99 (t, 2H); 4.29 (m,4H); 4.54 (s, 2H); 6.67 (td, 1H); 6.81 (s, 1H); 6.86 (dd, 1H); 6.90 (dd,1H); 8.09 (s, 1H).

Example 276-[({1-[2-(6-Chloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-2H-1,4-benzoxazin-3(4H)-one(Intermediate 56) (0.8 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (150 mg, 0.84 mmol) and sodium cyanoborohydride (90 mg, 1.4mmol) were reacted as described under Example 21 to give 78 mg (21%)product as a solid.

MS (ES): 472.24 (MH⁺) for C₂₃H₂₆ClN₅O₄

¹H-NMR (CDCl₃-d) δ: 1.50 (m, 2H); 1.93 (m, 3H); 2.15 (m, 2H); 2.56 (m,1); 2.59 (t, 2H); 2.96 (m, 2H); 3.82 (s, 2H); 4.01 (t, 2H); 4.56 (s,2H); 4.63 (s, 2H); 6.92 (m, 3H); 7.12 (d, 1H); 7.20 (d, 1H).

Intermediate 56:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-2H-1,4-benzoxazin-3(4H)-one

tert-Butyl{1-[2-(6-chloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 57) (640 mg, 1.56 mmol) was reacted as described forIntermediate 14. The crude trifluoro acetate of the title compound wasused without further purification for the next step (quantitativeyield).

MS (ES): 310 (MH⁺) for C₁₅H₂₀ClN₃O₂

Intermediate 57: tert-Butyl{1-[2-(6-chloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate

Commercially available 6-chloro-2H-1,4-benzoxazin-3(4H)-one (380 mg, 2.1mmol) was deprotonated with sodium hydride and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (2.3 mmol) as described for Intermediate 2.Chromatography on silica gel with hexanes/ethyl acetate (1:1) gave 640mg (74%) product.

MS (ES): 410.22 (MH⁺) for C₂₀H₂₈ClN₃O₄

¹H-NMR (CDCl₃-d) δ: 1.43 (m, 2H); 1.43 (s, 9H); 1.92 (m, 2H); 2.21 (m,2H); 2.58 (m, 2H); 2.88 (m, 2H); 3.45 (m, 1H); 3.99 (m, 2H); 4.41 (m,1H); 4.56 (s, 2H); 6.91 (m, 2H); 7.13 (s, 1H).

Example 286-[({1-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

4-[2-(4-aminopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-one(Intermediate 46) (0.2 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (WO2004/058144) (42 mg, 0.22 mmol) and sodium cyanoborohydride (23 mg, 0.36mmol) were reacted as described under Example 21 to give 28 mg (32%) ofproduct as a dry film.

MS (ES): 484.27 (MH⁺) for C₂₄H₂₉N₅O₄S

¹H-NMR (CDCl₂-d) δ: 1.50 (m, 2H); 1.92 (m, 2H); 2.17 (m, 3H); 2.55 (m,1H); 2.61 (m, 2H); 2.98 (m, 2H); 3.46 (s, 2H); 3.78 (s, 3H); 3.84 (s,2H); 4.04 (m, 2H); 4.51 (s, 2H); 6.50 (dd, 1H); 6.67 (d, 1H); 6.89 (d,1H); 6.98 (d, 1H); 7.57 (d, 1H).

Example 293-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

4-[2-(4-aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile(Intermediate 58) (0.8 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (140 mg, 0.79 mmol) and sodium cyanoborohydride (83 mg,1.32 mmol) were reacted as described under Example 21 to give 60 mg(19%) product as a solid.

MS (ES): 463.32 (MH⁺) for C₂₄H₂₆N₆O₄

¹H-NMR (CDCl_(3-d) δ:) 1.49 (m, 2H); 1.94 (m, 2H); 2.14 (m, 2H); 2.56(m, 1H); 2.59 (t, J=6.7 Hz, 2H); 2.94 (m, 2H); 3.84 (s, 2H); 4.03 (t,2H); 4.62 (s, 2H); 4.67 (s, 2H); 6.94 (d, 1H); 7.03 (d, 1H); 7.19 (d,1H); 7.30 (dd, 1H); 7.46 (d, 1H).

Intermediate 58:4-[2-(4-Aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitriletrifluoroacetate

tert-Butyl{1-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 59) (610 mg, 1.52 mmol) was reacted as described forIntermediate 14. The crude trifluoro acetate of the title compound wasused without further purification for the next step (quantitative,yield).

MS (ES): 301 (MH⁺) for C₁₆H₂₀N₄O₂

Intermediate 59: tert-Butyl{1-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate

3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 60)(350 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylatedwith 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethylmethanesulfonate (Intermediate 6) (2.2 mmol) as described forIntermediate 2. Chromatography on silica gel with hexanes/ethyl acetate(1:3) afforded 610 mg (76%) of the product.

MS (ES): 401.27 (MH⁺) for C₂₁H₂₈N₄O₄

¹H-NMR (CDCl₃d) δ: 1.41 (m, 2H); 1.42 (s, 9H); 1.93 (m, 2H); 2.21 (m,2H); 2.58 (m, 2H); 237 (m, 2H); 3.45 (m, 1H); 4.02 (m, 2H); 4.43 (m,1H); 4.67 (s, 2H); 7.03 (d, 1H); 7.30 (m, 1H); 7.47 (s, 1H).

Intermediate 60: 3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

The title compound was prepared similarly to literature procedure(Caliendo, G; et. al.; Bioorg. Med Chem. Lett., 2002, 10, 2663), but inone step. Commercially available 3-amino-4-hydroxybenzonitrile (2.5 g,18.6 mmol) was dissolved in chloroform (300 mL) and saturated sodiumbicarbonate (90 mL). The biphasic reaction mixture was cooled to 0° C.and bromoacetyl bromide (2.4 mL, 28 mmol) was added dropwise. Thereaction was stirred overnight at room temperature. The layers wereseparated and the aqueous layer was filtered to yield the desiredproduct as a tan solid, 2.3 g (69%).

MS (ES): 175.11 (MH⁺) for C₉H₆N₂O₂

¹H-NMR (DMSO-d₆) δ: 4.70 (s, 2H); 7.11 (d, 1H); 7.19 (d, 1H); 7.40 (m,1H); 10.98 (bs, 1H).

Example 306-{[(1-{2-[3-Oxo-6-(trifluoromethoxy)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-(trifloromethoxy)-2H-1,4-benzoxazin-3(4H)-one(Intermediate 61) (0.55 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (120 mg, 0.66 mmol) and sodium cyanoborohydride (69 mg, 1.1mmol) were reacted as described under Example 21 to give 44 mg (15%)product as a solid.

MS (ES): 522.25 (MH⁺) for C₂₄H₂₆F₃N₅O₅

¹H-NMR (CDCl₃-d) δ: 1.53 (m, 2H); 1.95 (m, 2H); 2.14 (m, 2H); 2.59 (t,2H); 2.59 (m, 1H); 2.96 (m, 2H); 3.85 (s, 2H); 4.02 (t, 2H); 4.59 (s,2H); 4.63 (s, 2H); 6.85 (d, 1H); 6.96 (d, 3H); 6.97 (d, 1H); 7.20 (d,1H).

Intermediate 61:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-(trifluoromethoxy)-2H-1,4-benzoxazin-3(4H)-one

tert-Butyl(1-{2-[3-oxo-6-(trifluoromethoxy)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)carbamate(Intermediate 62) (790 mg, 1.72 mmol) was reacted as described forIntermediate 14. The crude trifluoro acetate of the title compound wasused without further purification for the next step (quantitativeyield).

MS (ES): 360 (MH⁺) for C₁₆H₂₀F₃N₃O₃

Intermediate 62: tert-Butyl(1-{2-[3-oxo-6-(trifluoromethoxy)-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)carbamate

6-(Trifluoromethoxy)-2H-1,4-benzoxazin-3(4H)-one (Intermediate 63) (490mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (2.2 mmol) as described for Intermediate 2.Chromatography on silica gel with hexanes/ethyl acetate (2:3) afforded790 mg (86%) of the product.

MS (ES): 460.26 (MH⁺) for C₂₁H₂₈F₃N₃O₅

¹H-NMR (CDCl₃-d) δ: 1.38 (m, 2H); 1.43 (s, 9H); 1.92 (m, 2H); 2.20 (m,2H); 2.57 (m, 2H); 2.87 (m, 2H); 3.45 (m, 1H); 4.00 (m, 2H); 4.41 (m,1H); 4.58 (s, 2H); 6.85 (m, 1H); 6.95 (s, 1H); 6.99 (m, 1H).

Intermediate 63: 6-(Trifluoromethoxy)-2H-1,4-benzoxazin-3(4H)-one

Ethyl [2-nitro-4-(trifluoromethoxy)phenoxy]acetate (Intermediate 64)(1.14 g, 3.7 mmol) and iron powder (510 mg, 9.2 mmol) were reactedaccording to procedure for Intermediate 48, but heating for only onehour. Silica gel chromatography with hexanes/ethyl acetate (4:1)afforded product, 770 mg (90%).

MS (ES): 234.16 (MH⁺) for C₉H₆F₃NO₃

¹H-NMR (CDCl₃-d) δ: 4.63 (s, 2H); 6.73 (m, 1H); 6.84 (m, 1H); 6.97 (m,1H); 8.93 (bs, 1H).

Intermediate 64: Ethyl [2-nitro-4-(trifluoromethoxy)phenoxy]acetate

Prepared from 2-nitro-4-(trifluoromethoxy)phenol (2 g, 8.9 mmol)according to procedure for Intermediate 49. Silica gel chromatographywith hexanes/ethyl acetate (4:1) afforded product, 1.14 g (41%).

MS (ES): 310.12 (MH⁺) for C₁₁H₁₀F₃NO₆

¹H-NMR (CDCl₃-d) δ: 1.28 (t, 3H); 4.26 (q, 2H); 4.78 (s, 2H); 7.03 (d,1H); 7.40 (m, 1H); 7.78 (d, 1H).

Example 316-[({1-[2-(6-Fluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-fluoro-2H-1,4-benzoxazin-3(4H)-one(Intermediate 54) (0.7 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (WO2004/058144) (160 mg, 0.82 mmol) and sodium cyanoborohydride (90 mg, 1.4mmol) were reacted as described under Example 21, (but the reactionmixture was refluxed overnight before reduction with sodiumcyanoborohydride at room temperature for 2 hours) to give 76 mg (23%) ofproduct.

MS (ES): 472.25 (MH⁺) for C₂₃H₂₆FN₅O₃S

¹H-NMR (CDCl₃-d) δ: 1.48 (m, 2H); 1.92 (m, 2H); 2.15 (m, 2H); 2.55 (m,1H); 2.59 (t, 2H); 2.96 (m, 2H); 3.46 (s, 2H); 3.84 (s, 2H); 4.00 (t,2H); 4.55 (s, 2H); 6.68 (td, 1H); 6.86 (dd, 1H); 6.91 (dd, 1H); 6.98 (d,1H); 7.57 (d, 1H).

Example 324-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

4-[2-(4-Aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile(Intermediate 58) (2.8 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(550 mg, 3.36 mmol), and sodium cyanoborohydride (350 mg, 5.6 mmol) werereacted as described under Example 21 to give the crude free base. Theproduct was precipitated from chloroform by addition of 2M HCl in ether.The precipitate was collected by filtration to give title compound asthe bis HCl salt, 420 mg.

MS (ES): 450.21 (MH⁺) for C₂₄H₂₇N₅O₄

¹H-NMR (CDCl₃-d) δ: 1.43 (m, 2H); 1.89 (m, 2H); 2.12 (m, 2H); 2.48 (bs,1H); 2.53 (m, 1H); 2.56 (t, 2H); 2.90 (m, 2H); 3.79 (s, 2H); 4.02 (t,2H); 4.29 (m, 4H); 4.66 (s, 2H); 6.81 (s, 1H); 7.02 (d, 1H); 7.29 (dd,1H); 7.37 (d, 1H); 4.66 (s, 1H).

Example 336-[({1-[2-(6-Bromo-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-bromo-2H-1,4-benzoxazin-3(4H)-one(Intermediate 65) (0.57 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (120 mg, 0.67 mmol) and sodium cyanoborohydride (72 mg,1.14 mmol) were reacted as described under Example 21 to give 65 mg(22%) product as a solid.

MS (ES): 516.22 (MH⁺) for C₂₃H₂₆BrN₅O₄

¹H-NMR (CDCl₃-d) δ: 1.51 (m, 2H); 1.93 (m, 2H); 2.14 (m, 2H); 2.57 (m,1H); 2.59 (t, 2H); 2.96 (m, 2H); 3.83 (s, 2H); 4.00 (t, 2H); 4.56 (s,2H); 4.63 (s, 2H); 6.84 (d, 1H); 6.95 (d, 1H); 7.08 (dd, 1H); 7.20 (d,1H); 7.27 (d, 1H).

Intermediate 65:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-bromo-2H-1,4-benzoxazin-3(4H)-one

tert-Butyl{1-[2-(6-bromo-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 66) (261 mg, 0.57 mmol) was reacted as described forIntermediate 14. The crude trifluoro acetate of the title compound wasused without further purification for the next step (quantitativeyield).

MS (ES): 354 (MH⁺) for C₁₅H₂₀BrN₃O₂

Intermediate 66: tert-Butyl{1-[2-(6-bromo-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate

6-Bromo-2H-1,4-benzoxazin-3(4H)-one (Intermediate 67) (200 mg, 0.87mmol) was deprotonated with sodium hydride and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (0.96 mmol) as described for Intermediate 2.Chromatography on silica gel with hexanes/ethyl acetate (1:3) afforded261 mg (67%) product.

Intermediate 67: 6-Bromo-2H-1,4-benzoxazin-3(4H)-one

2-Amino-4-bromophenol (2.1 g, 11 mmol) and bromo acetyl bromide (1.4 mL,16.5 mmol) were reacted according to the procedure for Intermediate 60to afford product as a solid, 2.1 g (85%).

MS (ES): 228 (MH⁺) for C₈H₆BrNO₂

¹H-NMR (DMSO-d₆) δ: 4.58 (s, 2H); 6.90 (d, 1H); 7.00 (d, 1H); 7.06 (dd,1H); 10.9 (bs, 1H).

Example 346-[({1-[2-(6-Hydroxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

A solution of6-[({1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one(Example 22) (100 mg, 0.21 mmol) in dichloromethane was cooled to −78°C. and treated with 1M boron tribromide (0.63 mL, 0.63 mmol) dropwise.The reaction mixture was stirred at room temperature overnight. Thereaction mixture was cooled to −78° C. and an additional 1 equivalent of1M boron tribromide was added. The reaction was stirred for 4 hours atroom temperature, and then quenched with saturated sodium bicarbonate.The organic layer was separated and the aqueous phase was extractedthree times with dichloromethane. The combined organic extracts weredried over magnesium sulfate and concentrated to dryness under reducedpressure to afford crude product, 11 mg (11%), as a solid.

MS (ES): 454.35 (MH⁺) for C₂₃H₂₇N₅O₅

¹H-NMR (DMSO-d₆) δ: 1.47 (m, 2H); 1.98 (m, 4H); 2.94 (m, 3H); 3.94 (m,4H); 4.49 (s, 2H); 4.66 (s, 2H); 6.38 (dd, J=6.0, 2.5 Hz, 1H); 6.60 (d,J=2.2 Hz, 1H); 6.80 (d, J=8.7 Hz, 1H); 7.12 (d, J=8.1 Hz, 1H); 7.40 (d,J=8.3 Hz, 1H); 9.33 (s, 1H); 11.29 (s, 1H).

Example 354-{2-[4-({[2-(2,5-Difluorophenyl)cyclopropyl]methyl}amino)piperidin-1-yl]ethyl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

4-[2-(4-Aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile(Intermediate 58) (1 mmol),2-(2,5-difluorophenyl)cyclopropanecarbaldehyde (Intermediate 68) (200mg, 1.1 mmol) and sodium cyanoborohydride (125 mg, 2 mmol) were reactedas described under Example 21 to give 196 mg (42%) product as a gum.

MS (ES): 506.35 (MH⁺) for C₂₆H₂₈F₂N₄O₂

¹H-NMR (CDCl₃-d) δ: 0.94 (m, 2H); 1.31 (m, 1H); 1.41 (m, 2H); 1.89 (m,3H); 2.13 (m, 2H); 2.55 (m, 1H); 2.57 (t, 2H); 2.70 (d, 2H); 2.92 (m,2H); 4.03 (t, 2H); 4.67 (s, 2H); 6.55 (m, 1H); 6.77 (m, 1H); 6.93 (m,1H); 7.03 (d, 1H); 7.30 (dd, 1H); 7.38 (d, 1H).

Intermediate 68: 2-(2,5-Difluorophenyl)cyclopropanecarbaldehyde

To a solution of oxalyl chloride (1.2 mL, 13.5 mmol) in dichloromethaneat −78° C. was added dimethyl sulfoxide (1.9 mL, 27 mmol) dropwise andit was stirred at −78° C. for 30 minutes. A solution of[2-(2,5-difluorophenyl)cyclopropyl]methanol (Intermediate 69) (830 mg,4.5 mmol) in dichloromethane was added dropwise. The reaction mixturewas stirred at −78° C. for 30 minutes. Triethylamine (6.3 mL, 45 mmol)was added and the reaction mixture was stirred at room temperature for 2hours. The solvent was removed under reduced pressure. Silica gelchromatography with hexanes/ethyl acetate (9:1) afforded the desiredproduct, 546 mg (66%).

GC/MS: 182 (M⁺) for C₁₀H₈F₂O

¹H-NMR (CDCl₃-d) δ: 1.52 (m, 1H); 1.73 (m, 1H); 2.17 (m, 1H); 2.73 (m,1H); 6.65 (m, 1H); 6.87 (m, 1H); 6.98 (m, 1H); 9.36 (d, 1H).

Intermediate 69: [2-(2,5-Difluorophenyl)cyclopropyl]methanol

To a solution of (2E)-3-(2,5-difluorophenyl)prop-2-en-1-01 (Intermediate70) (2.12 g, 12.5 mmol) in dichloromethane at −10° C. was added dropwisediethyl zinc (1M, 75 mL, 75 mmol) over 20 minutes. Diiodomethane (6 mL,75 mmol) was added and the reaction mixture was stirred at roomtemperature overnight. Saturated ammonium chloride was added carefullyto quench the reaction. The reaction mixture was diluted with diethylether and the layers were separated. The organic phase was washed with10% aqueous hydrochloric acid, saturated sodium bicarbonate and brine,then dried over magnesium sulfate and concentrated to dryness underreduced pressure. Silica gel chromatography with hexanes/ethyl acetate(4:1) afforded the product, 940 mg (41%).

GC/MS: 184 (M⁺) for C₁₀H₁₀F₂O

¹H-NMR (DMSO-d₆) δ: 0.92 (m, 2H); 1.36 (m, 1H); 1.91 (m, 1H); 3.43 (m,2H); 4.64 (t, 1H); 6.82 (m, 1H); 6.97 (m, 1H); 7.15 (m, 1H).

Intermediate 70: (2E)-3-(2,5-Difluorophenyl)prop-2-en-1-ol

A mixture of (2E)-3-(2,5-difluorophenyl)acrylic acid (1 g, 5.43 mmol)and N,N-diisopropylethylamine (1.7 mL, 9.8 mmol) in tetrahydrofuran(THF) was treated with isobutyl chloroformate (1.4 mL, 10.8 mmol) atroom temperature. The reaction mixture was stirred for 30 minutes, andthen filtered. The filtrate was cooled to 0° C. and 2M lithiumborohydride (4.1 mL, 8.2 mmol) was added dropwise. The reaction mixturewas stirred at 0° C. for 30 minutes then at room temperature for 30minutes. Ice and 1N hydrochloric acid were added to the reaction mixtureto adjust the pH to 7. The aqueous layer was extracted with ethylacetate twice. The combined organic extracts were dried over sodiumsulfate and concentrated to dryness under reduced pressure. Silica gelchromatography with hexanes/ethyl acetate (3:2) afforded desiredproduct, 750 mg (82%).

GC/MS: 170 (M⁺) for C₉H₈F₂O

¹H-NMR (DMSO-d₆) δ: 4.15 (t, 2H); 5.01 (t, 1H); 6.61 (m, 2H); 7.10 (m,1H); 7.23 (m, 1H); 7.48 (m, 1H).

Example 366-[({1-[2-(6,8-Difluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6,8-difluoro-2H-1,4-benzoxazin-3(4H)-one(Intermediate 71) (1 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (220 mg, 1.24 mmol) and sodium cyanoborohydride (130 mg,2.1 mmol) were reacted as described for Example 21 to give 41 mg (8%)product as a dry film.

MS (ES): 474.26 (MH⁺) for C₂₃H₂₅F₂N₅O₄

¹H-NMR (DMSO-d₆) δ: 1.19 (m, 2H); 1.74 (m, 2H); 1.96 (m, 3H); 2.34 (m,1H); 2.42 (m, 2H); 2.82 (m, 2H); 3.65 (s, 2H); 3.97 (m, 2H); 4.59 (s,2H); 4.70 (s, 2H); 7.00 (d, 1H); 7.09 (m, 2H); 7.28 (d, 1H); 11.16 (s,1H).

Intermediate 71:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6,8-difluoro-2H-1,4-benzoxazin-3(4H)-one

tert-Butyl{1-[2-(6,8-difluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 72) (423 mg, 1 mmol) was reacted as described forIntermediate 14. The crude trifluoro acetate of the title compound wasused without further purification for the next step (quantitativeyield).

MS (ES): 312 (MH⁺) for C₁₅H₁₉F₂N₃O₂

Intermediate 72: tert-Butyl{1-[2-(6,8-difluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate

6,8-difluoro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 73) (205 mg, 1.11mmol) was deprotonated with sodium hydride and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (1.2 mmol) as described for Intermediate 2.Chromatography on silica gel with hexanes/ethyl acetate (1:3) afforded423 mg (92%) product.

MS (ES): 412.36 (MH⁺) for C₂₀H₂₇F₂N₃O₄

Intermediate 73: 6,8-Difluoro-2H-1,4-benzoxazin-3(4H)-one

Commercially available 2-amino-4,6-difluorophenol (1 g, 6.9 mmol) andbromo acetyl bromide (0.9 mL, 10.3 mmol) were reacted according to theprocedure for Intermediate 60 to afford the product as a solid, 208 mg(16%).

MS (ES): 184.34 (M-H⁻) for C₈H₅F₂NO₂

¹H-NMR (DMSO-d₆) δ: 4.64 (s, 2H); 6.55 (m, 1H); 6.94 (m, 1H); 10.99 (bs,1H).

Example 374-[2-(4-{[(2E)-3-(2,5-Difluorophenyl)prop-2-en-1-yl]amino}piperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

4-[2-(4-Aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile(Intermediate 58) (1.5 mmol), (2E)-3-(2,5-difluorophenyl)acrylaldehyde(202 mg, 1.2 mmol) (FR 2872164) (200 mg, 1.1 mmol) and sodiumcyanoborohydride were reacted as described under Example 21.Chromatography on silica gel with dichloromethane/methanol gave 168 mg(25%) product

MS (ES): 453 (MH⁺) for C₂₅H₂₆N₄O₂

¹H-NMR (CDCl₃) δ: 1.43 (q, 2H); 1.93 (d, 2H); 2.15 (t, 2H); 2.58 (t,3H); 2.93 (d, 2H); 3.48 (d, 2H); 4.03 (t, 2H); 4.67 (s, 2H); 6.35 (dt,1H); 6.65 (d, 1H); 6.88 (m, 1H); 6.96 (m, 1H); 7.03 (d, 1H); 7.12 (m,1H); 7.30 (dd, 1H); 7.40 (d, 1H).

Example 386-[({trans-4-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]cyclohexyl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(Trans-4-aminocyclohexyl)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-one(Intermediate 74) (310 mg, 1.73 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (1.73 mmol) and sodium cyanoborohydride were reacted asdescribed under Example 21 to give 110 mg (24%) product.

MS (ES): 467 (MH⁺) for C₂₅H₃₀N₄O₅

¹H-NMR (CDCl₃) δ: 1.05 (q, 2H); 1.19 (d, 2H); 1.35 (m, 1H); 1.53 (q,2H); 1.86 (d, 2H); 2.00 (d, 2H); 2.47 (m, 1H); 3.77 (s, 3H); 3.84-3.91(m, 4H); 4.50 (s, 2H); 4.61 (s, 2H); 6.47 (m, 2H); 6.90 (t, 2H); 7.18(d, 2H).

Intermediate 74:4-[2-(trans-4-Aminocyclohexyl)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-one

tert-Butyl{trans-4-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]cyclohexyl}carbamate(Intermediate 75) was reacted as described for Intermediate 14. Thecrude trifluoro acetate of the title compound was used without furtherpurification for the next step (quantitative yield).

MS (ES): 305 (MH⁺) for C₁₇H₂₄N₂O₃

Intermediate 75: tert-Butyl{trans-4-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin4-yl)ethyl]cyclohexyl}carbamate

6-Methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 48) (310 mg, 1.73mmol) was deprotonated with sodium hydride and alkylated with2-{trans-4-[(tert butoxycarbonyl)amino]cyclohexyl}ethyl methanesulfonate(Intermediate 76) (2 mmol) as described for Intermediate 2.Chromatography on silica gel with dichloromethane/methanol (20:1)afforded the product as a solid (58%).

MS (ES): 405 (MH⁺) for C₂₂H₃₂N₂O₅

Intermediate 76: 2-{trans-4-[(tert Butoxycarbonyl)amino]cyclohexyl}ethylmethanesulfonate

Commercially available tert-butyl[trans-4-(2-hydroxyethyl)cyclohexyl]carbamate (500 mg, 2.05 mmol) wasreacted according to the procedure described for Intermediate 6 to givethe product as a white solid (yield 92%).

¹H-NMR (CDCl₃) δ: 1.07 (m, 4H); 1.42 (m, 9H); 1.62 (m, 3H); 1.79 (m,3H); 1.98 (m, 1H); 2.99 (s, 3H); 3.35 (s, br, 1H); 4.24 (t, 2H); 4.35(s, 1H).

Example 393-Oxo-4-[2-(trans-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}cyclohexyl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

4-[2-(Trans-4-aminocyclohexyl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile(Intermediate 77),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (1.73 mmol) and sodium cyanoborohydride were reactedfollowing the procedure described for Example 21 to give the product in7% yield, as an off-white solid.

MS (ES): 462 (MH⁺) for C₂₅H₂₇N₅O₄

¹H-NMR (CDCl₃) δ: 1.05 (q, 2H); 1.45 (m, 5H); 1.88 (d, 2H); 2.07 (d,2H); 2.65 (t, 1H); 3.90 (m, 2H); 3.95 (s, 2H); 4.61 (s, 2H); 4.66 (s,2H); 6.97 (d, 1H); 7.04 (d, 1H); 7.17 (d, 1H); 7.20 (d, 1H); 7.31 (dd,1H).

Intermediate 77:4-[2-(trans-4-Aminocyclohexyl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

tert-Butyl{trans-4-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]cyclohexyl}carbamate(Intermediate 78) was reacted as described for Intermediate 14. Thecrude trifluoro acetate of the title compound was used without furtherpurification for the next step (quantitative yield).

MS (ES): 300 (MH⁺) for C₁₇H₂₁N₃O₂

Intermediate 78: tert-Butyl{trans-4-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]cyclohexyl}carbamate

3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 60)(350 mg, 2.0 mmol) was deprotonated with sodium hydride and alkylatedwith 2-{trans-4-[(tert butoxycarbonyl)amino]cyclohexyl}ethylmethanesulfonate (Intermediate 76) as described for Intermediate 2.Chromatography on silica gel with dichloromethane/methanol (20:1)afforded the product as a solid (50%).

MS (ES) 400 (MH⁺) for C₂₂H₂₉N₃O₄

Example 406-Bromo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

(Intermediate 79),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) and sodium cyanoborohydride were reacted as described underExample 21 to give the product as an off-white solid in 64% yield.

MS (ES): 517, 519(MH⁺) for C₂₂H₂₅BrN₆O₄

¹H-NMR (DMSO-d₆) δ: 1.25 (q, 2H); 1.81 (d, 5H); 1.98 (t, 2H); 2.6 (s,2H); 2.89 (m, 2H); 3.15 (s, 1H); 3.83 (s, 2H); 4.05 (t, 2H); 4.62 (s,2H); 4.76 (s, 2H); 6.97 (d, 1H); 7.04 (d, 1H); 7.23 (d, 1H); 7.34 (dd,2H); 11.23 (s, br, 1H)

Intermediate 79:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

tert-Butyl{1-[2-(6-bromo-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 80) was reacted as described for Intermediate 14. Thecrude trifluoro acetate of the title compound was used without furtherpurification for the next step (quantitative yield).

MS (ES): 355/357 (MH⁺) for C₁₄H₁₉BrN₄O₂

Intermediate 80: tert-Butyl{1-[2-(6-bromo-3-oxo-2,3-dihydro-4H-pyrido[3,2-b][1,4]oxazin-4-yl)ethyl]piperidin-4-yl}carbamate

6-Bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (WO 2004/058144) (935 mg,4.08 mmol) was deprotonated with sodium hydride and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (5.6 mmol) as described for Intermediate 2, butchromatography was omitted, to give the product as a solid in 92% yield.

MS (ES): 455, 457 (MH⁺) for C₁₉H₂₇BrN₄O₄

Example 416-[({1-[2-(6-Nitro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-nitro-2H-1,4-benzoxazin-3(4H)-one(Intermediate 81),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) and sodium cyanoborohydride were reacted as described underExample 21 to give the product as an off-white solid in 7% yield.

MS (ES): 483(MH⁺) for C₂₃H₂₆N₆O₆

¹H-NMR (CDCl₃) δ: 1.55 (q, 2H); 1.92 (d, 2H); 2.15 (t, 2H); 2.64 (t,3H); 2.95 (d, 2H); 3.86 (s, 2H); 4.08 (t, 2H); 4.62 (s, 2H); 4.71 (s,2H); 6.93 (d, 1H); 7.03 (d, 1H); 7.17 (d, 1H); 7.90 (dd, 1H); 8.13 (d,1H).

Intermediate 81:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-nitro-2H-1,4-benzoxazin-3(4H)-one

tert-Butyl{1-[2-(6-nitro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 82) was reacted as described for Intermediate 14. Thecrude trifluoro acetate of the title compound was used without furtherpurification for the next step (quantitative yield).

MS (ES): 321 (MH⁺) for C₁₅H₂₀N₄O₄

Intermediate 82: tert-Butyl{1-[2-(6-nitro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate

6-Nitro-2H-1,4-benzoxazin-3(4H)-one (Intermediate 83) (776 mg, 4 mmol)was deprotonated with sodium hydride and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (5.6 mmol) as described for Intermediate 2. The productprecipitated upon quenching of the reaction mixture with water and wasisolated by filtration in 98% yield, yellow solid.

MS (ES): 421 (MH⁺) for C₂₀H₂₈N₄O₆.

Intermediate 83: 6-Nitro-2H-1,4-benzoxazin-3(4H)-one

The title compound was prepared according to the procedure described forIntermediate 60, in 28% yield, yellow solid.

MS (ES⁻): 193(M-H⁻) for C₈H₆N₂O₄

¹H-NMR (DMSO-d₆) δ: 4.80 (s, 2H); 7.18 (d, 1H); 7.75 (s, 1H); 7.85 (d,1H); 11.10 (s, 1H)

Example 423-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbonitrile

and

Example 433-Oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxamide

A mixture of6-bromo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one(Example 40) (200 mg, 0.387 mmol), zinc cyanide (135 mg, 1.14 mmol) andtetrakis(triphenylphosphine) palladium(0) (50 mg, 0.043 mmol) inanhydrous DMF (3 mL) over molecular sieves 3A was vortexed and thenheated in the microwave at 200° C. for one hour. Reverse phasechromatography and generation of the free base as described for Example21 gave 27 mg (15%) of Example 42 and 23 mg (12%) of Example 43, bothoff-white solids.

Example 42

MS (ES): 464(MH⁺) for C₂₃H₂₅N₇O₄

¹H-NMR (DMSO-d₆) δ: 1.17 (q, 2H); 1.77 (d, 2H); 20.1 (t, 2H); 2.86 (d,2H); 3.75 (s, 2H); 4.09 (t, 2H); 4.61 (s, 2H); 4.88 (s, 2H); 7.00 (d,1H); 7.30 (d, 1H); 7.53 (d, 1H); 7.69 (d, 1H); 11.20 (s, br, 1H).

Example 43

MS (ES): 482(MH⁺) for C₂₃H₂₇N₇O₅

¹H-NMR (DMSO-d₆) δ: 1.09 (q, 2H); 1.66 (d, 2H); 1.91 (t, 2H); 2.31 (m,1H); 2.43 (m, 2H); 2.83 (d, 2H); 3.04 (s, 2H); 3.63 (s, 2H) 4.28 (t,2H); 4.59 (s, 2H); 4.80 (s, 2H); 6.96 (d, 1H); 7.26 (d, 1H); 7.45 (d,1H); 7.57 (s, 1H); 7.64 (d, 1H); 7.90 (s, 1H); 11.30 (s, br, 1H).

Example 44 Methyl3-oxo-4-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Methyl4-[2-(4-aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate(Intermediate 84),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) and sodium cyanoborohydride were reacted as described underExample 21 to give the product as an off-white solid in 13% yield.

MS (ES): 496(MH⁺) for C₂₅H₂₉N₅O₆

¹H-NMR (CDCl₃) δ: 1.53 (m, 3H); 2.16 (m, 3H); 2.49 (m, 2H); 2.62 (m,3H); 3.00 (d, 2H); 3.87 (s, 2H); 3.90 (s, 3H); 4.09 (t, 2H); 4.62 (s,2H); 4.64 (s, 2H); 6.95 (d, 1H); 6.98 (d, 1H); 7.19 (d, 1H); 7.19 (d,1H); 7.69 (d, 1H); 7.78 (d, 1H).

Intermediate 84: Methyl4-[2-(4-aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Methyl4-(2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate(Intermediate 85) was reacted as described for Intermediate 14. Thecrude trifluoro acetate of the title compound was used without furtherpurification for the next step (quantitative yield).

MS (ES): 334(MH⁺) for C₁₇H₂₃N₃O₄

Intermediate 85: Methyl4-(2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

Methyl 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate (Intermediate86) (330 mg, 1.59 mmol) was deprotonated with sodium hydride andalkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethylmethanesulfonate (Intermediate 6) (5.6 mmol) as described forIntermediate 2. Chromatography on silica gel withdichloromethane/methanol (20:1) gave the product in 85% yield as ayellow solid.

MS (ES): 434 (MH⁺) for C₂₂H₃₁N₃O₆

Intermediate 86: Methyl3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylate

3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 60)was heated with chlorotrimethylsilane in methanol according toliterature procedure (Fen-tair Luo et al. Tetrahedron Letters, 39, 1998,page 9455-9456). After removal of volatiles, the product was purified bychromatography on silica gel with methanol/dichloromethane (1:20) andobtained as off white solid, 40% yield.

MS (ES): 208 (MH⁺) for C₁₀H₉NO₄

¹H-NMR (DMSO-d₆) δ: 3.80 (s, 3H); 4.67 (s, 2H); 7.03 (d, 1H); 7.50 (d,1H); 7.55 (dd, 1H); 10.99 (s, 1H).

Example 456-[({1-[2-(6-Acetyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

6-Acetyl-4-[2-(4-aminopiperidin-1-yl)ethyl]-2H-1,4-benzoxazin-3(4H)-one(Intermediate 87),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) and sodium cyanoborohydride were reacted as described underExample 21 to give the product as an off-white solid in 7% yield.

MS (ES): 480(MH⁺) for C₂₅H₂₉N₅O₅

¹H-NMR (CDCl₃) δ: 1.49 (m, 2H); 1.98 (d, 2H); 2.13 (t, 2H); 2.57 (s,3H); 2.60 (m, 3H); 2.94 (d, 2H); 3.82 (s, 2H); 4.09 (t, 2H); 4.60 (s,2H); 4.64 (s, 2H); 6.90 (d, 1H); 7.01 (d, 1H); 7.16 (d, 1H); 7.58 (d,1H); 7.74 (s, 1H).

Intermediate 87:6-Acetyl-4-[2-(4-aminopiperidin-1-yl)ethyl]-2H-1,4-benzoxazin-3(4H)-one

tert-Butyl{1-[2-(6-acetyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 88) was reacted as described for Intermediate 14. Thecrude trifluoro acetate of the title compound was obtained as acolorless solid and used without further purification for the next step(quantitative yield).

MS (ES): 318 (MH⁺) for C₁₇H₂₃N₃O₃

Intermediate 88: tert-Butyl{1-[2-(6-acetyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate

6-Acetyl-2H-1,4-benzoxazin-3(4H)-one (Intermediate 89) (382 mg, 2.0mmol) was deprotonated with sodium hydride and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (2.2 mmol) as described for Intermediate 2.Chromatography on silica gel with hexanes/ethyl acetate (1:1) gave theproduct in 94% yield as a colorless solid.

MS (ES): 418 (MH⁺) for C₂₂H₃₁N₃O₅

Intermediate 89: 6-Acetyl-2H-1,4-benzoxazin-3(4H)-one

Ethyl (4-acetyl-2-nitrophenoxy)acetate (Intermediate 90) was reactedwith iron in acetic acid as described for Intermediate 48. The crudeproduct was obtained as an off white solid after work up.Recrystallization with ethyl acetate/methanol afforded the product as acolorless solid in 51% yield.

MS (ES): 192 (MH⁺) for C₁₀H₉NO₃

¹H-NMR (DMSO-d₆) δ: 2.50 (s, 3H); 4.68 (s, 2H); 7.06 (d, 1H); 7.47 (d,1H); 7.60 (dd, 1H); 10.88 (s, 1H).

Intermediate 90: Ethyl (4-acetyl-2-nitrophenoxy)acetate

1-(4-hydroxy-3-nitrophenyl)ethanone was reacted with cesium carbonateand 2-bromo ethyl acetate as described for Intermediate 49.Chromatography on silica gel with hexanes/ethyl acetate (1:1) gave theproduct in 69% yield as a pink solid

MS (ES): 268 (MH⁺) for C₁₂H₁₃NO₆

¹H-NMR (CDCl₃) δ: 1.30 (t, 3H); 2.60 (s, 3H); 4.30 (q, 2H); 4.86 (s,2H); 7.00 (d, 1H); 8.20 (d, 1H); 8.50 (s, 1H).

Example 466-Acetyl-4-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-2H-1,4-benzoxazin-3(4H)-one

6-Acetyl-4-[2-(4-aminopiperidin-1-yl)ethyl]-2H-1,4-benzoxazin-3(4H)-one(Intermediate 87), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde(WO 2004/058144) and sodium cyanoborohydride were reacted as describedfor Example 21. The was converted to the free base was treated with HClin dioxane (2M, excess) and the excess HCl and dioxane were removedunder reduced pressure to give the bis hydrochloride salt of theproduct, 25 mg (9%), as an off-white solid.

MS (ES): 467(MH⁺) for C₂₃H₂₇N₇O₅

¹H-NMR (DMSO-d₆) δ: 2.10 (m, 2H); 2.32 (d, 1H); 2.65 (s, 3H); 3.07 (m,2H); 3.27 (s, 3H) 3.57 (s, 1H); 3.77 (d, 2H); 4.19 (s, 2H); 4.35 (dd,4H); 4.46 (t, 2H); 4.81 (s, 2H); 7.12 (d, 1H); 7.24 (s, 1H); 7.66 (d,1H); 7.76 (s, 1H); 8.18 (s, 1H); 9.73 (brs, 2H); 11.06 (brs, 1H).

Example 474-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methyl-2H-1,4-benzoxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methyl-2H-1,4-benzoxazin-3(4H)-one(Intermediate 91), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde(WO 2004/058144) and sodium cyanoborohydride were reacted as describedfor Example 21 to give the product as an oil, 4.7 mg (2%).

MS (ES): 439 (MH⁺) for C₂₄H₃₀N₄O₄

¹H-NMR (CDCl₃) δ: 2.13 (m, 2H); 2.25 (s, 2H); 2.31 (s, 3H); 2.61 (s,2H); 3.06 (m, 2H) 3.33 (m, 1H); 3.51 (m, 2H); 4.14 (s, 2H); 4.20-4.40(m, 6H); 4.53 (s, 2H); 6.70-6.95 (m,

Intermediate 91:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methyl-2H-1,4-benzoxazin-3(4H)-one

tert-Butyl{1-[2-(6-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 92) was reacted as described for Intermediate 14. Thecrude trifluoro acetate of the title compound was obtained as acolorless solid and used without further purification for the next step(quantitative yield).

MS (ES): 290 (MH⁺) for C₁₆H₂₃N₃O₂

Intermediate 92: tert-Butyl{1-[2-(6-methyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate

Commercially available 6-methyl-2H-1,4-benzoxazin-3(4H)-one (326 mg, 2.0mmol) was deprotonated with sodium hydride and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (2.2 mmol) as described for Intermediate 2.Chromatography on silica gel with dichloromethane/methanol (20:1) gavethe product in 66% yield as a colorless solid.

MS (ES): 390 (MH⁺) for C₂₁H₃₁N₃O₄

Example 483-Oxo-4-[2-(6-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}-3-azabicyclo[3.1.0]hex-3-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

4-[2-(6-Amino-3-azabicyclo[3.1.0]hex-3-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile(Intermediate 93),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) and sodium cyanoborohydride were reacted as described underExample 21 to give the product as an off-white solid in 6% yield.

MS (ES): 461(MH⁺) for C₂₄H₂₄N₆O₄

¹H-NMR (CDCl₃), δ: 2.46 (m, 4H); 2.66 (t, 2H); 3.01 (d, 2H); 3.83 (s,2H); 3.98 (m, 3H) 4.63 (s, 2H); 4.64 (s, 2H); 6.89 (d, 1H); 7.02 (d,1H); 7.18 (d, 1H); 7.31 (m, 2H).

Intermediate 93:4-[2-(6-Amino-3-azabicyclo[3.1.0]hex-3-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

tert-Butyl{3-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-3-azabicyclo[3.1.0]hex-6-yl}carbamate(Intermediate 94) was reacted as described for Intermediate 14. Thecrude trifluoro acetate of the title compound was obtained as acolorless solid and used without further purification for the next step(quantitative yield).

MS (ES): 299 (MH⁺) for C₁₆H₁₈N₄O₂.

Intermediate 94: tert-Butyl{3-[2(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-3-azabicyclo[3.1.0]hex-6-yl}carbamate

3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 60)(231 mg, 1.5 mmol) was deprotonated with sodium hydride and alkylatedwith 2-{6-[(tert-butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}ethylmethanesulfonate (Intermediate 95) (1.55 mmol) as described forIntermediate 2. Chromatography on silica gel withdichloromethane/methanol (20:1) gave 442 mg (94%) product as a yellowgum.

MS (ES): 399 (MH⁺) for C₂₁H₂₆N₄O₄

Intermediate 95:2-{6-[(tert-Butoxycarbonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}ethylmethanesulfonate

To a mixture of tert-butyl[3-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate (Intermediate96) (376 mg, 1.55 mmol) and triethyl amine (0.283 mL, 3 mmol) inanhydrous chloroform (15 mL) was added at 0° C. methanesulfonyl chloride(228 mg, 3 mmol) via syringe. The reaction was allowed to warm to roomtemperature over 1 hr and worked up as described for Intermediate 6. Thecrude mesylate was used for the next step without delay.

Intermediate 96: tert-Butyl[3-(2-hydroxyethyl)-3-azabicyclo[3.1.0]hex-6-yl]carbamate

A mixture of tert-butyl 3-azabicyclo[3.1.0]hex-6-ylcarbamate (T. F.Braish et al. Synlett, 1996, page 1100 and T. Norris et al. J. Chem.Soc. Perkin I, 2000, page 1615-1622), 2-bromoethanol (669 mg, 3.36 mmol)and N,N-ethyldiisopropyl amine (0.087 mL) in acetonitrile (9 mL) washeated in the microwave at 70° C. for 30 minutes. Chromatography onsilica gel with chloroform/methanol (20:1) gave 376 mg (46%) of theproduct.

MS(EI) 242 for C₁₂H₂₂N₂O₃

Example 494-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-2H-1,4-benzoxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-2H-1,4-benzoxazin-3(4H)-one(Intermediate 97), 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde(WO 2004/058144) and sodium cyanoborohydride were reacted as describedfor Example 21 to give the product as a off-white solid, 81 mg (16%).

MS (ES): 425(MH⁺) for C₂₃H₂₈N₄O₄.2HCl

¹H-NMR (DMSO-d₆) δ: 2.2-3.8 (m, 14H); 3.87 (s, 1H); 4.42 (m, 4H); 4.75(s, 2H); 7.11 (m, 3H); 7.40-7.60 (m, 2H); 8.29 (s, 1H); 10.01 (s, 2H);10.01 (s, 2H); 11.35 (brs, 1H).

Intermediate 97:4-[2-(4-Aminopiperidin-1-yl)ethyl]-2H-1,4-benzoxazin-3(4H)-one

tert-Butyl{1-[2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 98) was reacted as described for Intermediate 14. Thecrude trifluoro acetate of the title compound was obtained as acolorless solid and used without further purification for the next step(quantitative yield).

MS (ES): 276 (MH⁺) for C₁₅H₂₁N₃O₂

Intermediate 98: tert-Butyl{1-[2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate

2H-1,4-Benzoxazin-3(4H)-one (298 mg, 2.0 mmol) was deprotonated withsodium hydride and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (2.0 mmol) as described for Intermediate 2.Chromatography on silica gel with dichloromethane/methanol (20:1) gavethe product in 63% yield as a yellow gum.

MS (ES): 376 (MH⁺) for C₂₀H₂₉N₃O₄

Example 506-{[(1-{2-[6-(1-Hydroxyethyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

6-[({1-[2-(6-Acetyl-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one(Example 45) (309 mg, 0.645 mmol) was reduced with sodium borohydride(47 mg, 2 equivalents) in methanol (12 mL) at 0° C. After quenching thereaction with water, the reaction mixture was concentrated under reducedpressure and extracted with chloroform. The chloroform layer was washedwith brine and dried over magnesium sulfate and concentrated to drynessto give the as an off-white solid, 202 mg (95%).

MS (ES): 482(MH⁺) for C₂₅H₃₁N₅O₅

¹H-NMR (CDCl₃) δ: 1.47 (d, 3H); 1.50 (q, 2H); 1.89 (d, 2H); 2.18 (m,2H); 2.62 (m, 1H) 2.65 (t, 2H); 3.00 (d, 2H); 3.82 (s, 2H); 4.09 (t,2H); 4.55 (s, 2H); 4.61 (s, 2H); 4.86 (q, 1H) 6.91 (m, 3H); 7.18 (d,1H); 7.26 (s, 1H).

Example 51

EthylN-{1-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}-N-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]glycinate

To a mixture of4-[2-(4-{[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]amino}piperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile(Example 37) (120 mg, 0.265 mmol) and ethyl diazoacetate (0.09 mL) indichloromethane (5 ml) was added rhodium(II) acetate (4 mg, 0.009 mmol)at room temperature. After 72 hrs, the product was concentrated andpurified by preparative TLC to give 6.7 mg of product (5%).

MS (ES): 539 (MW) for C₂₉H₃₂N₄O₄

¹H-NMR (CDCl₃), δ: 1.22 (t, 3H); 1.25 (m, 2H); 1.62 (m, 4H); 1.84 (d,2H); 2.16 (bs, 2H) 2.60 (m, 2H); 2.70 (m, 1H); 3.03 (m, 2H); 3.37 (s,2H); 3.45 (d, 2H); 4.07 (m, 2H); 4.11 (q, 2H); 4.68 (s, 2H); 6.32 (dt,1H); 6.67 (d, 1H); 6.86 (m, 1H); 6.97 (dm, 1H); 7.02 (d, 1H); 7.13 (m,1H); 7.30 (dd, 1H); 7.45 (s, 1H).

Example 526-{[(1-{2-[6-(Methylsulfonyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one(Intermediate 99),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) and sodium cyanoborohydride were reacted as described underExample 21 to give the product as an off-white solid in 8% yield.

MS (ES): 516 (MH⁺) for C₂₄H₂₉N₅O₆S

¹H-NMR (CDCl₃) δ: 1.53 (m, 2H); 1.87 (d, 2H); 2.13 (t, 4H); 2.54 (m,1H); 2.60 (t, 2H) 2.93 (d, 2H); 3.05 (s, 3H); 3.82 (s, 2H); 4.08 (t,2H); 4.60 (s, 2H); 4.66 (s, 2H); 6.90 (d, 1H); 7.10 (d, 1H); 7.16 (d,1H); 7.56 (d, 1H); 7.72 (s, 1H).

Intermediate 99:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one

tert-Butyl(1-{2-[6-(methylsulfonyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)carbamate(Intermediate 100) was reacted as described for Intermediate 14. Thecrude trifluoro acetate of the title compound was obtained as acolorless solid and used without further purification for the next step(quantitative yield).

MS (ES): 353 (MH³⁰) for C₁₆H₂₃N₃O₄S

Intermediate 100: tert-Butyl(1-{2-[6-(methylsulfonyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)carbamate

6-(Methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one (Intermediate 101) (280mg, 1.23 mmol) was deprotonated with sodium hydride and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (1.62 mmol) as described for Intermediate 2.Chromatography on silica gel with dichloromethane/methanol (20:1) gavethe product in 66% yield as a yellow gum.

MS (ES): 454 (MH⁺) for C₂₁H₃₁N₃O₆S

Intermediate 101: 6-(Methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one

4-Methylsulfonyl-2-aminophenol (Intermediate 102) (690 mg, 3.68 mmol)was dissolved in chloroform (30 mL) and saturated sodium bicarbonate (20mL). The biphasic reaction mixture was cooled to 0° C. and bromoacetylbromide (889 mg, 4.42 mmol) was added dropwise. The reaction was stirredovernight at room temperature. The layers were separated and the aqueouslayer was filtered to yield the desired product as a solid, 280 mg(33%).

MS (ES): 228(MH⁺) for C₉H₉NO₄S

¹H-NMR (DMSO-d₆) δ: 3.16 (s, 3H); 4.73 (s, 2H); 7.15 (d, 1H); 7.41 (s,1H); 7.50 (d, 1H); 11.05 (s, 1H).

Intermediate 102 4-Methylsulfonyl-2-aminophenol

The title compound was prepared by reacting 2-methoxy-5-methylsulfonylaniline (5.0 g, 24.8 mmol) with boron tribromide (26 mmol, 26 mL, 1M indichloromethane) in chloroform (30 m L) at 0 C.°. After 20 minutes, thereaction was quenched with sodium bicarbonate and the ph of the aqueousphase was adjusted to pH 7 and extracted with ethyl acetate.Concentration under reduced pressure gave 690 mg of product as an orangesolid (15%).

MS (ES): 188(MH³⁰) for C₇H₉NO₃S

Example 536-{[(1-{2-[6-(Ethylsulfonyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)amino]methyl}-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one(Intermediate 103),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) and sodium cyanoborohydride were reacted as described underExample 21 to give the product as an off-white solid in 19% yield.

MS (ES): 530(MH⁺) for C₂₅H₃₁N₅O₆S

¹H-NMR (DMSO-d₆) δ: 1.11 (t, 3H); 1.30 (q, 2H); 1.74 (d, 2)H; 2.00 (t,2H); 2.40 (m, 3H) 2.82 (d, 2H); 3.32 (m, 4H); 3.67 (s, 2H); 4.05 (t,2H); 4.60 (s, 2H); 4.78 (s, 2H); 7.01 (d, 1H); 7.28 (d, 1H); 7.30 (d,1H); 7.50 (d, 1H); 7.68 (s, 1H); 11.18 (brs, 1H).

Intermediate 103:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one

tert-Butyl(1-{2-[6-(ethylsulfonyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)carbamate(Intermediate 104) was reacted as described for Intermediate 14. Thecrude trifluoro acetate of the title compound was obtained as acolorless solid and used without further purification for the next step(quantitative yield).

MS (ES): 368 (MH⁺) for C₁₇H₂₆N₃O₄S

Intermediate 104: tert-Butyl(1-{2-[6-(ethylsulfonyl)-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl]ethyl}piperidin-4-yl)carbamate

6-(Ethylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one (Intermediate 105) (482mg, 2 mmol) was deprotonated with sodium hydride and alkylated with2-{[4(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (2.2 mmol) as described for Intermediate 2.Chromatography on silica gel with hexanes/ethyl acetate gave the productin 81% yield as a yellow gum.

MS (ES): 468 (MH⁺) for C₂₂H₃₃N₃O₆S

Intermediate 105: 6-(Ethylsulfonyl)-2H-1,4-benzoxazin-3 (4H)-one

Commercially available 4-ethylsulfonyl-2-aminophenol (4.02 g, 20 mmol)was dissolved in DMF (30 mL) and mixed with cesium carbonate (6.5 g, 20mmol). The reaction mixture was cooled to 0° C. and bromoacetyl bromide(4.0 g, 20 mmol) in DMF (5 mL) was added dropwise. The reaction wasstirred overnight at room temperature. After aqueous work up, theproduct was purified by silica gel chromatography withmethanol/dichloromethane to give the product as an orange solid, 1.7 g(35%).

MS (ES): 242(MH⁺) for C₁₀H₁₁NO₄S

¹H-NMR (DMSO-d₆) δ: 1.09 (t, 3H); 3.24 (q, 2H); 4.72 (s, 2H); 7.16 (d,1H); 7.37 (s, 1H); 7.41 (d, 1H); 11.00 (s, 1H).

Example 546-[({1-[2-(7-Methoxy-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxy-1,4-dihydro-2H-3,1-benzoxazin-2-onetrifluoro acetate (Intermediate 106) (324 mg, 0.78 mmol) was convertedto the free base using N,N-diisopropylethylamine for 30 minutes andreacted with3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (153 mg, 0.86 mmol) and sodium cyanoborohydride (98 mg,1.56 mmol) as described under Example 21. The reaction mixture wasfiltered through a 0.45 μm membrane and concentrated to dryness underreduced pressure. Chromatography on silica gel withdichloromethane/methanol (9:1) gave the free base of the title compoundas a colorless foam. The free base was taken up in 1,4 dioxane (2 mL),followed by addition of 4M HCl in 1,4-dioxane (0.30 mL). The resultingprecipitate was collected by filtration and gave 75 mg (48%) of thebis-hydrochloride salt of the product.

MS (ES): 468.17 (MH⁺) for C₂₄H₂₉N₅O₅

¹H NMR (DMSO-d₆) δ 2.09 (m, 2H); 2.31-2.44 (m, 2H); 3.00-3.15 (m, 2H);3.66-3.78 (m, 2H); 3.82 (s, 3H); 4.13-4.22 (m, 2H); 4.22-4.35 (m, 2H);4.69 (m, 2H); 5.25 (s, 2H); 6.70 (d, 1H); 6.85 (s, 1H); 7.20 (dd, 2H);7.45 (d, 1H); 9.56-9.71 (m, 2H); 11.05-11.19 (m, 1H); 11.37 (s, 1H).

Intermediate 106:1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxy-1,4-dihydro-2H-3,1-benzoxazin-2-one

A solution of tert-butyl{1-[2-(7-methoxy-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 107) (319 mg, 0.78 mmol) in dichloromethane (8 mL) wastreated at room temperature under vigorous stirring with atrifluoroacetic acid (0.75 mL, 10 mmol). After 2 hours, the reactionmixture was concentrated under reduced pressure to give 324 mg(quantitative) of product as a brown oil.

MS (ES): 302.24 (MH⁺) for C₁₆H₂₃N₃O₃

Intermediate 107: tert-Butyl{1-[2-(7-methoxy-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)ethyl]piperidin-4-yl}carbamate

A solution of 7-methoxyquinolin-2(1H)-one (Intermediate 108, 310 mg, 1.8mmol) in dry N,N-dimethylformamide (5 mL) was treated at 0° C. understirring with lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran,1.9 mL, 1.9 mmol). The mixture was then stirred for 30 minutes at roomtemperature and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6, 2.03 mmol) as described for Intermediate 2.Chromatography on silica gel with dichloromethane/methanol (95:5) gave333 mg (47%) of the product as a colorless solid.

MS (ES): 406 (MH⁺) for C₂₁H₃₁N₃O₅

¹H-NMR (CDCl₃) δ: 1.34-1.46 (m, 11H); 1.86 (d, 2H); 2.12-2.25 (m, 2H);2.60-2.64 (m, 2H); 2.60-2.64 (m, 2H); 2.81-2.90 (m, 2H); 3.38-3.45 (m,1H); 3.76 (s, 3H); 3.97-3.91 (m, 2H); 4.32-4.42 (m, 1H); 5.05 (s, 2H);6.49-6.56 (m, 2H); 6.94 (d, 1H).

Intermediate 108: 7-Methoxyquinolin-2(1H)-one

A solution of (2-amino-4-methoxyphenyl)methanol (Intermediate 109, 744mg, 4.85 mmol) in toluene (25 mL) was treated with triethylamine (1.36mL, 9.7 mmol) and triphosgene (1.58 g, 5.34 mL). The reaction wasstirred at room temperature for 1.5 hours and then was heated to 110° C.for an additional 2 hours. The reaction was cooled to room temperature,diluted with water (25 mL), filtered, extracted aqueous layer withtoluene (3×30 mL) and ethyl acetate (2×20 mL). The combined organiclayers were washed with brine, dried over sodium sulfate, andconcentrated under reduced pressure. Chromatography on silica gel withhexanes/ethyl acetate (3:2) gave 314 mg (36%) of the product as acolorless solid.

¹H-NMR (DMSO-d₆) δ: 3.78 (s, 3H); 5.26 (s, 2H); 6.38 (d, 1H); 6.59 (d,1H); 6.98 (d, 1H); 8.36 (brs, 1H).

Intermediate 109: (2-Amino-4-methoxyphenyl)methanol

To a solution of commercially available 4-methoxy-2-nitrobenzoic acid(4.0 g, 20.66 mmol) in tetrahydrofuran (20 mL) at −15° C. under nitrogenwas added N-methylmorphorine (2.2 ml, 20 mmol) followed by isobutylchloroformate (2.6 mL, 20 mmol) in portions. After 5 min, the reactionwas filtered and the solid was rinsed with tetrahydrofuran (20 mL). Thefiltrate was cooled to −15° C. and a solution of sodium borohydride inwater (3 M, 10 mL) was added to the filtrate. The reaction was stirredfor 5 min. The reaction mixture was partitioned between water anddichloromethane, and extracted aqueous layer with dichloromethane (3×100mL). The combined organic layers were washed with brine, dried overmagnesium sulfate, and concentrated under reduced pressure. The residuewas redissolved in tetrahydrofuran (35 mL) and added palladium (10% oncarbon, 400 mg) and stirred under hydrogen gas for 18 hours. Thereaction mixture was then filtered through celite and concentrated underreduced pressure. The residue was chromatographed on silica gel withhexanes/ethyl acetate (3:2) gave 744 mg (24% yield) of product as ayellow solid.

¹H-NMR (DMSO-d₆) δ 3.63 (s, 3H); 4.30 (s, 2H); 4.84-4.96 (m, 2H); 6.08(dd, 1H); 6.20 (d, 1H); 6.90 (d, 1H).

Example 557-Methoxy-3-methyl-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]quinazoline-2,4(1H,3H)-dione

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxyquinazoline-2,4(1H,3H)-dione(Intermediate 110, crude, 153 mg, 0.46 mmol) was converted to the freebase with N,N-diisopropylethylamine for 30 min and reacted with3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (90 mg, 0.51 mmol) as described under Example 21. Thereaction mixture was cooled to 0° C., and sodium triacetoxy borohydride(194 mg, 0.92 mmol) was added. The resulting reaction mixture wasstirred at room temperature for 18 hours and then worked up as describedfor Example 54 to give the bis-hydrochloride salt of the product, 12.5mg (25%), as a colorless solid.

MS (ES): 495 (MH⁺) for C₂₅H₃₀N₆O₅

¹H NMR (DMSO-D6) δ 1.85-2.32 (m, 1H); 3.68-3.88 (m, 3H); 3.89-4.08 (m,3H); 4.10-4.43 (m, 5H); 4.50-4.78 (m, 5H); 6.91-7.44 (m, 5H); 7.99 (bs,1H); 9.74 (br s, 2H); 11.16-11.38 (m, 2H).

Intermediate 110:1-[2-(4-Amino-2-oxopiperidin-1-yl)ethyl]-7-methoxy-3-methylquinazoline-2,4(1H,3H)-dione

tert-Butyl{1-[2-(7-methoxy-3-methyl-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 111, 350 mg, 0.83 mmol) was reacted as described forIntermediate 106. The crude trifluoro acetate of the title compound wasobtained as a black oil, 395 mg. (quantitative), and used withoutfurther purification for the next step.

MS (ES): 319 (MH⁺) for C₁₇H₂₄N₄O₃

Intermediate 111: tert-Butyl{1-[2-(7-methoxy-3-methyl-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

7-Methoxy-3-methylquinazoline-2,4(1H,3H)-dione (Intermediate 112, 523mg, 2.5 mmol) was deprotonated with lithium bis(trimethylsilyl)amide (1Min tetrahydrofuran, 1.9 mL, 1.9 mmol) and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6, 3.4 mmol) as described for Intermediate 2.Chromatography on silica gel with dichloromethane/methanol (95:5) gave200 mg (18%) of the product as a colorless solid.

MS (ES): 433 (MH⁺) for C₂₂H₃₂N₄O₅,

¹H NMR (CDCl₃) δ 1.16-1.28 (m, 1H); 1.14-1.43 (m, 11H); 1.89-2.04 (m,3H); 2.25-2,47 (m, 2H); 2.80 (d, 3H); 2.94-3.14 (m, 2H); 3.77 (s, 3H);4.22-4.36 (m, 1H); 4.40-4.56 (m, 1H); 4.99-5.09 (m, 1H); 7.02-7.03 (m,1H); 7.31-7.47 (m, 2H).

Intermediate 112: 7-Methoxy-3-methylquinazoline-2,4(1H,3H)-dione

2-Amino-4-methoxybenzoic acid (Intermediate 113, 950 mg, 6.2 mmol) and1,3-dimethyl urea (5.4 g, 62 mmol) were heated at 150° C. for 16 hours.The reaction was cooled to 100° C. and diluted with water. The mixturewas partitioned between ethyl acetate and water, the aqueous phaseextracted with ethyl acetate (3×20 mL) and then chloroform/2-propanol(3:1, 2×20 mL). The combined organic layers were washed with brine,dried over sodium sulfate, and concentrated under reduced pressure.Chromatography on silica gel with hexanes/ethyl acetate (1:2) to give a350 mg (27%) product as an orange oil.

MS (ES): 205 (MH⁺) for C₁₀H₁₀N₂O₃,

¹H-NMR (DMSO-d₆) δ: 2.60 (d, 3H); 3.68 (s, 3H); 5.95 (d, 1H); 6.45 (dd,1H); 6.86 (dd, 1H); 8.47 (s, 1H).

Intermediate 113: 2-Amino-4-methoxybenzoic acid

4-Methoxy-2-nitrobenzoic acid (3 g, 16.4 mmol) was hydrogenated overpalladium on carbon (10%, 300 mg) in methanol (80 mL) at roomtemperature and normal pressure for 18 hours. The reaction mixture wasfiltered through celite and concentrated to dryness under reducepressure to give 2.50 g (100%) of the product as a colorless solid.

¹H NMR (DMSO-d₆) δ 3.70 (s, 3H); 6.09 (dd, 1H); 6.23 (d, 1H); 7.59 (d,1H).

Example 564-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-oxopiperidin-1-yl}ethyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one

4-[2-(4-Amino-2-oxopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-onetrifluoroacetate (Intermediate 114, crude, 390 mg, 0.83 mmol) wasconverted to the free base with N,N-diisopropylethylamine and reactedwith 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO2004/058144) (150 mg, 0.91 mmol) and sodium triacetoxy borohydride (360mg, 1.7 mmol) as described for Example 55 to give the his hydrochloridesalt of the product as a colorless solid, 89 mg (63%).

MS (ES): 469.19 (MH⁺) for C₂₄H₂₈N₄O₆

¹H NMR (DMSO-d₆) δ 1.84 (dd, 1H); 2.26 (d, 1H); 2.37-2.46 (m, 1H);2.68-2.77 (m, 1H); 3.29-3.49 (m, 5H); 3.75 (s, 3H); 4.32-4.42 (m, 4H);4.52 (s, 2H); 6.56 (dd, 1H); 6.91-6.98 (m, 2H); 7.22 (s, 1H); 8.23 (s,1H); 9.52 (bs, 2H).

Intermediate 114:4-[2-(4-Amino-2-oxopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-one

tert-Butyl{1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-oxopiperidin-4-yl}carbamate(Intermediate 115, 350 mg, 0.83 mmol) was reacted as described forIntermediate 106. The crude trifluoro acetate of the title compound wasobtained as a black oil, 395 mg (quantitative), and used without furtherpurification for the next step.

MS (ES): 320 (MH⁺) for C₁₆H₂₁N₃O₄.

Intermediate 115: tert-Butyl{1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-oxopiperidin-4-yl}carbamate

A mixture of tert-butyl{1-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 47, 1.39 g, 3.4 mmol) in water/ethyl acetate (40 mL, 4:1)was treated with sodium periodate (2.8 g, 21.4 mmol) and ruthenium (IV)oxide hydrate (50 mg, 0.34 mmol) at room temperature. After 53 hours,the reaction was diluted with ethyl acetate, the aqueous phase wasextracted with ethyl acetate (6×25 mL), and the combined organic layerswere mixed with 2-propanol (20 mL) and stirred for 2 hours at roomtemperature. The reaction mixture was then filtered through celite,dried over sodium sulfate, and concentrated in vacuo. Chromatography onsilica gel with dichloromethane/methanol (95:5) gave 350 mg (25%) of theproduct as a colorless solid.

MS (ES): 415 (MH⁺) for C₂₉H₂₆N₃O₆

¹H-NMR (DMSO-6) δ: 1.37 (s, 9H); 1.51-1.56 (m, 1H); 1.81-1.94 (m, 1H);2.02-2.11 (m, 1H); 2.33-2.41 (dd, 1H); 3.06-3.12 (m, 1H); 3.27-3.31 (m,2H); 3.40-3.45 (m, 2H); 3.55-3.65 (m, 1H); 3.75 (s, 3H); 3.99 (t, 2H);4.52 (s, 2H); 6.57 (dd, 1H); 6.90-6.98 (m, 3H).

Example 576-[({1-[2-(6-Methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-oxopiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-amino-2-oxopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-onetrifluoroacetate (Intermediate 114, crude, 335 mg, 1.05 mmol) wasconverted to the free base with N,N-diisopropylethylamine and reactedwith 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (205 mg, 1.15 mmol) and sodium triacetoxy borohydride (132mg, 2.10 mmol) as described for Example 55 to give the bis hydrochloridesalt of the product as a colorless solid, 36 mg (46%).

MS (ES): 482.15 (MH⁺) for C₂₄H₂₇N₅O₆

¹H NMR DMSO-d₆) δ: 1.75-1.95 (m, 1H); 2.20-2.41 (m, 1H); 2.74 (dd, 1H);3.76 (s, 3H); 3.92-4.07 (m, 2H); 4.12-4.23 (m, 1H); 4.53-4.62 (m, 2H);4.69 (s, 2H); 6.57 (dd, 2.26, 1H); 6.90-6.99 (m, 2H); 7.20 (d, 1H); 7.43(d, 1H); 9.39 (bs, 1H); 11.35 (s, 1H).

Example 583-Oxo-4-[2-(2-oxo-4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

4-[2-(4-Amino-2-oxopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitriletrifluoroacetate (Intermediate 116, crude, 232 mg, 0.54 mmol) wasconverted to the free base with N,N-diisopropylethylamine and reactedwith 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (110 mg, 0.60 mmol) and sodium triacetoxy borohydride (240mg, 1.10 mmol) as described for Example 55 to give the bis hydrochloridesalt of the product as a colorless solid, 65 mg (49%).

MS (ES): 477.35 (MH⁺) for C₂₄H₂₄N₆O₅

¹H NMR (DMSO-d₆) δ 1.79-1.84 (m, 1H); 2.28-2.42 (m, 2H); 2.70-2.77 (m,1H); 3.51-3.56 (m, 2H); 4.08-4.16 (m, 4H); 4.68 (s, 3H); 4.73 (s, 3H);7.14-7.22 (m, 2H); 7.43-7.52 (m, 2H); 9.46 (bs, 1H); 11.35 (s, 1H).

Intermediate 116:4-[2-(4-Amino-2-oxopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

tert-Butyl{1-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-oxopiperidin-4-yl}carbamate(Intermediate 117, 225 mg, 0.54 mmol) was reacted as described forIntermediate 106. The crude trifluoro acetate of the title compound wasobtained as a red oil, 232 mg (quantitative), and used without furtherpurification for the next step.

MS (ES): 315 (MH⁺) for C₁₇H₁₈N₄O₂

Intermediate 117: tert-Butyl{1-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-2-oxopiperidin-4-yl}carbamate

tert-Butyl{1-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 59, 835 mg, 2.1 mmol) was reacted with sodium periodate(2.8 g, 13.1 mmol) and ruthenium (IV) oxide hydrate (30 mg, 20.1 mmol)as described for Intermediate 115 for 16 hours, except, chloroform wasused for aqueous workup. The product was obtained as a colorless solid,230 mg (27%).

MS (ES): 415 (MH⁺) for C₂₁H₂₆N₄O₅

¹H-NMR (DMSO-d₆) δ: 1.36 (s, 9H); 1.42-1.57 (m, 2H); 1.87 (d, 1H); 2.00(dd, 1H); 2.32 (dd, 1H); 3.38-3.48 (m, 2H); 3.51-3.63 (m, 1H); 4.07 (t,2H); 4.72 (s, 2H); 6.94 (d, 1H); 7.14 (d, 1H); 7.48 (dd, 1H); 7.84 (d,1H).

Example 596-({4-[3-(7-Methoxy-2-oxo-2H-3,1-benzoxazin-1(4H)-yl)propyl]piperazin-1-yl}methyl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

7-Methoxy-1-(3-piperazin-1-ylpropyl)-1,4-dihydro-2H-3,1-benzoxazin-2-onetrifluoroacetate (Intermediate 118, crude, 886 mg, 1.66 mmol) wasconverted to the free base with N,N-diisopropylethylamine and reactedwith 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (220 mg, 1.23 mmol) and sodium triacetoxy borohydride (521mg, 2.46 mmol) as described for Example 55 to give the free base of theproduct as a pink foam after chromatography on silica gel withdichloromethane/methanol (93:7), 86 mg (21%).

MS (ES): 468.19 (MH⁺) for C₂₄H₂₉N₅O₅

1H NMR (DMSO-d₆) δ: 1.60-1.75 (m, 2H); 2.19-2.44 (m, 9H); 3.37-3.43 (m,2H); 3.72 (s, 2H); 3.83-3.96 (m, 2H); 4.53 (s, 2H); 4.60 (s, 2H); 6.56(d, 1H); 6.78 (d, 1H); 6.88-7.02 (m, 2H); 7.29 (d, 1H); 11.22 (s, 1H).

Intermediate 118:6-Methoxy-4-(3-piperazin-1-ylpropyl)-2H-1,4-benzoxazin-3(4H)-one

tert-Butyl{1-[2-(7-methoxy-2-oxoquinolin-1(2H)-yl)propyl]piperidin-4-yl}carbamate(Intermediate 119, 500 mg, 1.23 mmol) was reacted as described forIntermediate 106. The crude trifluoro acetate of the title compound wasobtained as a yellow oil, 866 mg (quantitative), and used withoutfurther purification for the next step.

MS (ES): 306 (MH⁺) for C₁₆H₂₃N₃O₃

Intermediate 119: tert-Butyl4-[2-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperazine-1-carboxylate

6-Methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 48, 440 mg, 2.5mmol) was deprotonated with sodium hydride (125 mg, 60% in oil, 3.2mmol) and alkylated with tert-butyl4-{3-[(methylsulfonyl)oxy]propyl}piperazine-1-carboxylate (Intermediate120, 2.5 mmol) as described for Intermediate 2. Chromatography on silicagel with dichloromethane/2-propanol (95:5) gave 1.25 g (quantitative) ofthe product as a yellow oil.

MS (ES): 406 (MH⁺) for C₂₀H₂₉N₃O₅

¹H-NMR (CDCl₃) δ: 1.45 (s, 9H); 1.78-1.90 (m, 2H) 2.36-2.40 (m, 6H);3.43 (m, 4H); 3.77 (s, 3H); 3.95 (t, 2H); 4.52 (s, 2H); 6.49 (dd, 1H);6.67 (d, 1H); 6.89 (d, 1H).

Intermediate 120: tert-Butyl4-{3-[(methylsulfonyl)oxy]propyl}piperazine-1-carboxylate

tert-Butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (Intermediate121, 2.38 g, 9.8 mmol) was reacted with methanesulfonyl chloride (0.91mL, 11.7 mmol) in the presence of triethylamine (1.9 mL, 13.7 mmol) asdescribed for Intermediate 6. The crude product was used without furtherpurification for the next step.

1H NMR (CDCl₃) δ: 1.44 (s, 9H); 1.94-2.04 (m, 2H); 2.43-2.51 (m, 6H);3.01 (s, 3H); 3.50-3.40 (m, 4H); 4.28-4.33 (m, 2H).

Intermediate 121: tert-Butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate

A mixture of tert-butyl piperazine-1-carboxylate (2.75 g, 14.8 mmol),1-bromo-3-propanol (1.43 mL, 16.2 mmol) and potassium carbonate (2.25mL, 27.5 mmol) in acetonitrile (75 mL) was heated at 95° C. for 4 hours.The solvent was removed under reduced pressure, and the residue wastaken up in dichloromethane (300 mL) and washed with water, brine, driedover sodium sulfate and concentrated under reduced pressure.Chromatography on silica gel with methanol in dichloromethane (0-10%)gave a tan solid 2.88 g (80% yield).

MS (ES): 245 (MH⁺) for C₁₂H₂₄N₂O₃.

¹H-NMR (CDCl₃) δ: 1.44 (m, 9H); 1.70-1.82 (m, 2H); 2.40-2.53 (m, 2H);2.62-2.65 (m, 2H); 3.43-3.50 (m, 4H); 2.77 (m, 2H); 3.73-3.82 (m, 2H).

Example 604-{3-[4-(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)piperazin-1-yl]propyl}-6-methoxy-2H-1,4-benzoxazin-3(4H)-one

7-Methoxy-1-(3-piperazin-1-ylpropyl)-1,4-dihydro-2H-3,1-benzoxazin-2-onetrifluoroacetate (Intermediate 118, crude, 963 mg, 1.81 mmol) wasconverted to the free base with N,N-diisopropylethylamine and reactedwith 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO2004/058144) (203 mg, 123 mmol) and sodium triacetoxy borohydride (240mg, 1.10 mmol) as described for Example 55 to give the free base of theproduct as an oil after chromatography on silica gel withdichloromethane/methanol (93:7), 125 mg (22%).

MS (ES): 455.15 (MH⁺) for C₂₄H₃₀N₄O₅

¹H NMR (DMSO-D6) δ: 1.67 (s, 2H); 2.26-2.41 (m, 8H); 3.41 (s, 2H); 3.72(s, 3H); 3.88 (s, 2H); 4.29 (d, 4H); 4.52 (s, 2H); 6.56 (d, 1H); 6.78(s, 1H); 6.83-6.99 (m, 3H); 7.99 (s, 1H).

Example 614-[2-({1-[(2E)-3-(2,5-Difluorophenyl)prop-2-en-1-yl]piperidin-4-yl}amino)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-one

1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]piperidin-4-aminetrifluoroacetate (Intermediate 122, 430 mg, 0.85 mmol) was converted tothe free base with N,N-diisopropylethylamine and reacted with(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetaldehyde(Intermediate 125, 197 mg, 0.90 mmol) and sodium triacetoxy borohydride(132 mg, 2.10 mmol) as described for Example 55 and purified by ReversePhase Chromatography with 20 to 75% acetonitrile/water containing 0.1%TFA to give the trifluoroacetic acid salt of the product, 31 mg.

MS (ES): 458.27 (MH⁺) for C₂₅H₂₉F₂N₃O₃

1H NMR (DMSO-D6) δ: 1.85-1.72 (m, 1H); 2.30-2.21 (m, 1H); 3.24-2.8 (m,2H); 4.05-3.72 (m, 5H); 4.13-4.40 (m, 2H); 4.60 (br s, 2H); 6.61-6.98(m, 2H); 7.21-7.41 (m, 2H); 7.60 (brs, 1H); 9.04 (brs, 1H).

Intermediate 122:1-[2E)-3-(2,5-Difluorophenyl)prop-2-en-1-yl]piperidin-4-amine

tert-Butyl{1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]piperidin-4-yl}carbamate(Intermediate 123, 299 mg, 0.85 mmol) was reacted as described forIntermediate 106. The crude trifluoro acetate of the title compound wasobtained as an oil, 430 mg (quantitative), and used without furtherpurification for the next step

MS (ES): 253 (MH⁺) for C₁₄H₁₈F₂N₂.

Intermediate 123: tert-Butyl{1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]piperidin-4-yl}carbamate

A mixture of tert-butyl piperidin-4-ylcarbamate (248 mg, 1.2 mmol),potassium carbonate (188 mg, 1.4 mmol) and2-[(1E)-3-chloroprop-1-en-1-yl]-1,4-difluorobenzene (Intermediate 124,257 mg, 1.4 mmol) in ethanol (7 mL) was heated to 80° C. for 18 hours.The mixture was concentrated under reduced pressure, the residue takenup in dichloromethane (20 mL) and water (20 mL), the aqueous phase wasback extracted with dichloromethane (2×20 mL) and the combined organicphases were dried over sodium sulfate. Chromatography on silica gel withdichloromethane/methanol (95:5) gave 300 mg (69%) of product as a brownfoam.

MS (ES): 353 (MH⁺) for C₁₉H₂₆F₂N₂O₂

¹H NMR (CDCl₃) δ 1.41-1.53 (m, 11H); 1.96 (d, 2H); 2.07-2.21 (m, 2H);2.92 (d, 2H); 3.18 (d, 2H); 3.48 (d, 1H); 4.45 (s, 1H); 6.27-6.39 (m,1H); 6.63 (d, 1H); 6.85-7.01 (m, 2H); 7.12 (ddd, 1H); 7.24-7.28 (m, 1H).

Intermediate 124: 2-[(1E)-3-Chloroprop-1-en-1-yl]-1,4-difluorobenzene

A mixture of (2E)-3-(2,5-difluorophenyl)prop-2-en-1-ol (Intermediate 70,700 mg, 4.12 mmol), 1,4-dioxane (5 mL), and hydrochloric acid (12.1 M, 1mL) was heated in the microwave at 100° C. for 3 hours. It wasconcentrated to dryness under reduced pressure, the residue taken up inethyl acetate (10 mL), washed with water (1×10 mL), saturated sodiumbicarbonate solution, brine and dried over sodium sulfate. The solventwas removed under reduced pressure to give 688 mg (89% yield) of productas a yellow oil.

¹H NMR (CDCl₃) δ 4.24 (dd, 2H); 6.38 (dt, 1H); 6.75 (d, 1H); 6.88-7.04(m, 2H); 7.13 (ddd, 1H).

Intermediate 125:(6-Methoxy-3-oxo-2,3-dihydro-4H-1-benzoxazin-4-yl)acetaldehyde

To a solution of oxalyl chloride (0.26 mL, 3.0 mmol) in dichloromethane(10 mL) at −70° C. was added a solution of dimethyl sulfoxide (DMSO,0.426 mL, 6.0 mmol) in dichloromethane (10 mL). After thirty minutes asolution of 4-(2-hydroxyethyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one(Intermediate 126, 550 mg, 2.5 mmol) in dichloromethane (3.5 mL) wasadded dropwise and it was stirred for 90 minutes. Triethyl amine (1.74ml, 12.5 mmol) was added it was stirred at −70° C. for another 45minutes. The reaction was quenched with water and warmed to 0° C. It wasdiluted with dichloromethane, the aqueous phase was extracted withdichloromethane (3×25 mL) and the combined organic phases were washedwith 1N HCl (2×25 mL), water (25 mL), 1M sodium carbonate solution (2×25mL), water, brine, dried over magnesium sulfate and concentrated atreduced pressure. Chromatography on silica gel withdichloromethane/methanol (96:4) gave the product as a yellow oil, 292 mg(53%).

MS (ES): 221 (MH⁺) for C₁₁H₁₂NO₄

¹H NMR (CDCl₂) δ 3.71-3.78 (m, 3H); 4.63 (s, 2H); 4.69 (s, 2H); 6.22 (d,1H); 6.53 (dd, 1H); 6.95 (d, 1H); 9.67 (s, 1H).

Intermediate 126:4-(2-Hydroxyethyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one

To a solution of4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-methoxy-2H-1,4-benzoxazin-3(4H)-one(Intermediate 127, 1.38 g, 4.1 mmol) in tetrahydrofuran (40 mL) wasadded tetrabutyl ammonium fluoride (1M in tetrahydrofuran (THF), 4.1 mL,4.1 mmol). The reaction was stirred at room temperature for two hours.The solvent was removed under reduced pressure and the residue was takenup in dichloromethane, washed with water and dried over magnesiumsulfate. Chromatography on silica gel using dichloromethane/methanol(95:5) gave the title compound as a yellow oil (570 mg, 62%).

¹H NMR (CDCl₂) δ ppm: 3.77 (s, 3H); 3.92 (t, 2H); 4.08 (t, 2H); 4.55 (s,2H); 6.52 (dd, 1H); 6.68 (d, 1H); 6.90 (d, 1H).

Intermediate 127:4-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl-6-methoxy-2H-1,4-benzoxazin-3(4H)-one

To a solution of 6-methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 48)(800 mg, 4.5 mmol) in DMF (16 mL) was added sodium hydride (60% inmineral oil, 260 mg, 6.5 mmol). After 20 minutes,(2-bromoethoxy)(tert-butyl)dimethylsilane (1.4 mL, 6.5 mmol) was addedand it was heated to 70° C. in the microwave for 40 minutes. Thereaction mixture was partitioned between water (100 mL) and ethylacetate (100 mL). The aqueous phase was extracted with ethyl acetate(4×50 mL). The combined organic phases were washed with water (6×250mL), dried over magnesium sulfate and concentrated at reduced pressureto afford the product as a yellow oil which was used without furtherpurification. (1.38 g, 91%).

¹H NMR (CDCl₃) δ: −0.02 (s, 6H); 0.83 (s, 9H); 3.77 (s, 3H); 3.84-3.91(m, 2H); 4.01 (t, 2H); 4.52 (s, 2H); 6.50 (dd, 1H); 6.82 (d, 1H); 6.87(d, 1H).

Example 624-(3-{4-[(2E)-3-(2,5-Difluorophenyl)prop-2-en-1-yl]piperazin-1-yl}propyl)-6-methoxy-2H-1,4-benzoxazin-3(4B)-one

A solution of6-methoxy-4-(3-piperazin-1-ylpropyl)-2H-1,4-benzoxazin-3(4H)-onetrifluoroacetate (Intermediate 118, 985 mg, 1.52 mmol) in dry ethanol(10 mL) was converted to the free base with N,N-diisopropylethylaminefor 30 min and then was added2-[(1E)-4-chloroprop-1-en-1-yl]-1,4-difluorobenzene (Intermediate 124,315 mg, 1.67 mmol), and potassium carbonate (230 mg, 1.67 mmol). Themixture was heated at 80° C. for 18 hours, cooled to room temperatureand then concentrated to dryness under reduced pressure. The residue waspartitioned between water (50 mL) and dichloromethane (100 mL). Theorganic phase was dried over sodium sulfate and concentrated underreduced pressure. Chromatography on silica gel withdichloromethane/methanol (95:5) gave the free base of the title compoundas a yellow foam. The free base was taken up in dichloromethane (14 mL),followed by the addition of 2M HCl in ether (0.41 mL). The precipitatewas collected by filtration and to give the bis hydrochloride salt ofthe product as a colorless solid, 171 mg (79%).

MS (ES): 458.30 (MH⁺) for C₂₅H₂₉F₂N₃O₃

¹H NMR (DMSO-D6) δ 1.90-2.04 (bs, 2H); 3.15-3.30 (m, 6H); 3.75 (s, 3H);3.95 (m, 3H); 4.57 (s, 2H); 6.45-6.54 (m, 1H); 6.57-6.61 (m, 1H); 6.81(d, 1H); 6.93 (d, J=9 Hz, 1H); 7.26-7.33 (m, 2H); 7.56 (m, 1H).

Example 636-[({1-[2-(6-Methoxy-2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

A solution of1-[2-(4-aminopiperidin-1-yl)ethyl]-6-methoxy-1,7-naphthyridin-2(1H)-one(Intermediate 128, crude, 116 mg, 0.38 mmol) and3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde[WO2004/058144] (82 mg, 0.46 mmol) in chloroform/methanol (6 mL, 10:1)was heated over 3 Å molecular sieves at 70° C. for 18 hours. Thereaction mixture was cooled to 0° C., and sodium triacetoxy borohydride(180 mg, 0.84 mmol) was added. The resulting reaction mixture wasallowed to warm to room temperature and stirred for 18 hours. Thereaction was diluted with dichloromethane (50 mL) and water (10 mL). Theaqueous phase was separated and evaporated to give a solid. The solidwas suspended in methanol and filtered. The resultant solid wasdissolved in dichloromethane:methanol (1:1) and treated with 2N HCl inether to obtain the dihydrochloride salt. The colorless precipitate wascollected by filtration and gave 28 mg (14%) of the bis-hydrochloridesalt of the product.

MS(ES)⁺: 465 (MH)⁺ for C₂₄H₂₈N₆O₄

¹H NMR (DMSO-D₆) δ ppm: 2.04-2.19 (m, 2H); 2.19-2.31 (m, 1H); 2.32-2.45(m, 3H); 3.05-3.21 (m, 4H) 3.69-3.84 (m, 2H); 3.89 (s, 3H); 4.05-4.20(m, 2H); 4.62-4.75 (m, 4H); 6.83 (d, 1H); 7.20 (s, 1H); 7.30 (d, 1H);7.42 (d, 1H); 7.92 (d, 1H); 8.78 (s, 1H); 9.94 (s, 1H); 11.39 (s, 2H).

Intermediate 128:1-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methoxy-1,7-naphthyridin-2(1H)-one

A solution of tert-butyl{1-[2-(6-chloro-2-oxo-1,7-naphthyridin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 129, 335 mg, 0.83 mmol) was treated with a solution ofsodium methoxide in methanol (0.5 M, 4 mL). The reaction was sealed in atube and heated at 150° C. for 4 hours using microwave irradiation. Thereaction was diluted with water and ethyl acetate. The layers wereseparated. The aqueous phase was washed with ethyl acetate twice. Theorganic extracts were combined dried over magnesium sulfate andevaporated at reduced pressure to give 116 mg (64%) of the crude productas a yellow oil.

MS (ES): 303 (MH⁺) for C₁₆H₂₂N₄O₂

Intermediate 129: tert-Butyl{1-[2-(7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

6-Chloro-1,7-naphthyridin-2(1H)-one (J. Org. Chem. 1990, 55, 4744-4750)(360 mg, 2.0 mmol) was deprotonated with sodium hydride (100 mg, 60% inoil, 2.4 mmol) and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl)ethyl methanesulfonate(Intermediate 6) 2.75 mmol) as described for Intermediate 2.Chromatography on silica gel with methanol in dichloromethane (0-10%)gave 334 mg (20%) of the product as a colorless solid.

MS (ES): 407 (MH⁺) for C₂₀H₂₇ClN₄O₃

¹H-NMR (DMSO-d₆) δ: 1.19-1.32 (m, 1H); 1.36 (s, 9H); 1.56-1.70 (m, 2H);2.01 (s, 2H); 2.51-2.57 (m, 2H); 2.67-2.75 (m, 1H); 2.83-2.93 (m, 2H);3.10-3.25 (m, 2H); 3.29-3.31 (m, 1H); 4.30-4.40 (m, 2H); 6.71-6.80 (m,1H); 6.91 (d, 1H); 7.87 (s, 1H); 7.91 (d, 1H); 8.74 (s, 1H).

Example 64 Methyl1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate

A solution of methyl4-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylatetrifluoroacetate (Intermediate 130, crude, 171, 0.48 mmol),(2E)-3-(2,5-difluorophenyl)acrylaldehyde [FR 2872164] (81 mg, 0.48mmol), and triethylamine (0.13 mL. 0.96 mmol) in chloroform/methanol (6mL, 10:1) was heated over 3 Å molecular sieves at 70° C. for 3 hours.The reaction mixture was cooled to 0° C., and sodium triacetoxyborohydride (200 mg, 0.94 mmol) was added. The resulting reactionmixture was allowed to warm to room temperature and stir for 18 hours.The reaction was diluted with ethyl acetate (25 mL) and water (10 mL).The aqueous phase was separated and washed twice with ethyl acetate. Theorganic layers were combined, dried over magnesium sulfate andevaporated at reduced pressure. Chromatography on silica gel withdiethyl ether gave the title compound as a off-white foam, (79 mg, 32%).

MS(ES) 510 (MH)⁺ for C₂₈H₂₉F₂N₃O₄.

¹H NMR (DMSO-d₆) δ 1.10-1.21 (m, 1H); 1.23-1.34 (m, 1H); 1.44-1.55 (m,3H); 1.67-1.79 (m, 2H); 1.95-2.07 (m, 1H); 2.18-2.29 (m, 1H); 2.31-2.43(m, 1H); 2.64-2.70 (m, 1H); 2.71-2.80 (m, 1H); 2.82-2.89 (m, 1H);3.06-3.17 (m, 2H); 3.57 (d, 3H); 3.84-3.96 (m, 2H); 4 4.77 (s, 2H);6.40-6.51 (m, 1H); 6.56-6.63 (m, 1H); 7.12 (ddd, 1H); 7.17 (d, 2H);7.20-7.28 (m, 1H); 7.47-7.56 (m, 2H); 7.72 (d, 1H).

Intermediate 130: Methyl4-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate

A solution of 1-tert-butyl 3-methyl4-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-1,3-dicarboxylate(Intermediate 131, 220 mg, 0.48 mmol) was reacted as described forIntermediate 106. The crude trifluoro acetate of the title compound wasused without further purification for the next step (quantitative).

Intermediate 131: tert-Butyl 3-methyl4-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-1,3-dicarboxylate

A solution of 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile(Intermediate 60) (265 mg, 1.53 mmol) in dry dimethylformamide (DMF) (5mL) was treated at 0° C. with sodium hydride (105 mg, 60% in oil, 2.63mmol) and then stirred for 30 minutes at room temperature. A solution of1-tert-butyl 3-methyl4-{3-[(methylsulfonyl)oxy]propyl}piperidine-1,3-dicarboxylate in DMF(Intermediate 132, 0.31 mmol/mL, 5 mL, 1.53 mmol) was then added and theresulting mixture was stirred at room temperature for 96 hours. Thereaction was diluted with ethyl acetate and water. The aqueous layer wasadjusted to pH3 with 1N HCl. The layers were separated. The aqueousphase was extracted once with ethyl acetate. The combined organic phaseswere washed four times with water, dried over magnesium sulfate andevaporated at reduced pressure. Chromatography on silica gel with(10-35%) acetone in hexanes gave 445 mg (64%) of the product as a whitesemi-solid (as a mixture of diastereomers).

MS (ES): 458 (M⁺) for C₂₄H₃N₃O₆

¹H NMR (CDCl₃) δ: 1.43 and 1.44 (two s, 9H); 1.47-1.9 (m, 7H); 2.56-2.83(m, 2H); 2.94-3.2 (m, 1H); 3.65 and 3.70 (two s, 3H); 3.76-3.99 (m, 2H);4.02-4.21 (m, 1H); 4.67 and 4.70 (two s, 2H); 7.04 (m, 1H); 7.11 and7.18 (two brs, 1H); 7.30 (m, 1H).

Intermediate 132: 1-tert-Butyl 3-methyl4-{3-[methylsulfonyl)oxy]propyl}piperidine-1,3-dicarboxylate

A mixture of 1-tert-butyl 3-methyl4-(3-hydroxypropyl)piperidine-1,3-dicarboxylate (Intermediate 133, 460mg, 1.53 mmol) in dry dichloromethane (5 mL) and triethyl amine (0.3 mL,2.14 mmol) was treated at 0° C. with a solution of methanesulfonylchloride (0.14 mL, 1.83 mmol) in dichloromethane (5 mL). After 2 hoursminutes the reaction was complete by TLC (dichloromethane:methanol10:1). The reaction was diluted with ethyl acetate and water. The layerswere separated. The organic layer was washed with 0.1N HCl, water,saturated sodium bicarbonate, dried over magnesium sulfate. The solventwas removed under reduced pressure and the crude preparation of themesylate was used without delay for the next step.

Intermediate 133: 1-tert-Butyl 3-methyl4-(3-hydroxypropyl)piperidine-1,3-dicarboxylate

A solution of 1-tert-butyl 3-methyl 4-allylpiperidine-1,3-dicarboxylate[WO2002/072572] (715 mg, 2.53 mmol) in tetrahydrofuran (5 mL) at 0° C.was treated with a solution of 9-BBN in tetrahydrofuran (0.5M, 10.2 mL,5.1 mmol). After one hour the reaction mixture was allowed to warm toroom temperature for 3 hours. The reaction mixture was cooled to 0° C.and treated with water (3 mL), NaOH (3N, 6 mL) and hydrogen peroxide(30% solution, 6 mL). The reaction was allowed to warm to roomtemperature and stir for one hour. The reaction was diluted with ethylacetate and water. The layers were separated. The aqueous layer wasextracted twice with ethyl acetate. The combined organic layers weredried over magnesium sulfate and concentrated at reduced. Chromatographyon silica gel with methanol in dichloromethane (0-10%) gave the productas a colorless oil as a mixture of diastereomers (460 mg, 60%).

MS (ES): 302(MH⁺) for C₁₅H₂₇NO₅

¹H NMR (CDCl₃) δ: 1.28-1.39 (m, 1H); 1.43 and 1.44 (two s, 9H);1.46-1.54 (m, 2H); 1.56-1.67 (m, 3H); 1.73-1.85 (m, 2H); 2.58-2.63 (m,1H); 3.02-3.12 (m, 1H); 3.27 (dd, 1H); 3.60-3.64 (m, 2H); 3.65 and 3.69(two s, 3H); 3.71-3.81 (m, 1H); 3.87-3.98 (m, 1H).

Example 654-[3-(6-Cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]-1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]piperidine-3-carboxylicacid

A solution of methyl1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4H-[3-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate(Example 64) (73 mg, 0.143 mmol) in methanol (12 mL) and water (5 mL)was treated with sodium hydroxide solution (1N, 1 mL). After 64 hours,the pH was adjusted to 6 with 1N HCl. The mixture was extracted withethyl acetate (3×30 mL). The combined organic extracts were dried overmagnesium sulfate and concentrated at reduced pressure. Chromatographyon silica gel using methanol in dichloromethane (0-10%) and triturationwith diethyl ether gave the title compound as a colorless solid, mixtureof diastereomers, 10 mg (14%).

MS (ES): 496 (MH)⁺ for C₂₇H₂₇F₂N₃O₄

¹H NMR (CDCl₃) δ: 1.40-1.45 (m, 1H); 1.47-1.52 (m, 1H); 1.60-1.65 (m,1H); 1.65-1.77 (m, 3H); 2.25-2.37 (m, 2H); 2.70-2.77 (m, 1H); 3.08-3.16(m, 1H); 3.23-3.30 (m, 1H); 3.30-3.40 (m, 2H); 3.64-3.72 (m, 1H);3.73-3.84 (m, 1H); 3.86-3.95 (m, 1H); 3.95-4.07 (m, 1H); 4.60-4.71 (m,3H); 6.21-6.31 (m, 1H); 6.67 (d, 1H); 6.87-6.95 (m, 1H); 6.96-7.01 (m,1H); 7.01-7.07 (m, 1H); 7.09-7.15 (m, 1H); 7.28-7.31 (m, 1H).

Example 667-Fluoro-3-methyl-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]quinazoline-2,4(1H,3H)-dione

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-fluoro-3-methylquinazoline-2,4(1H,3H)-dionetrifluoroacetate salt (Intermediate 134) (0.476 mmol, 380 mg crude) wasconverted to the free base with N,N-diisopropylethylamine (0.5 mL, 3.0mmol) and reacted with3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (102 mg, 0.571 mmol) and sodium triacetoxy borohydride (222mg, 1.05 mmol) as described for Example 55. The reaction was dilutedwith dichloromethane and water. The layers were separated. The aqueouslayer was extracted with dichloromethane twice. The combined organiclayers were dried over magnesium sulfate and evaporated at reducedpressure. Chromatography on silica gel using methanol in dichloromethane(0-9%) with 1% concentrated ammonium hydroxide (aqueous) gave theproduct as a waxy material. This material was taken up indichloromethane and washed well with water. The organic phase was driedover magnesium sulfate and evaporated to obtain the title compound as acolorless solid (48 mg, 21%).

MS(ES): 483 (MH)⁺ for C₂₄H₂₇FN₆O₄

¹H NMR (DMSO-D6) δ: 1.14-1.28 (m, 2H); 1.71-1.82 (m, 2H); 1.94-2.06 (m,2H); 2.33-2.44 (m, 2H); 2.83-2.92 (m, 2H); 3.26-3.30 (m, 3H); 3.65-3.72(m, 4.17 (t, 2H); 4.60 (s, 2H); 7.00 (d, 1H); 7.13 (td, 1H); 7.29 (d,1H); 7.36 (dd, 1H); 8.09 (dd, 1H); 11.18 (s, 1H).

Intermediate 134:1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-fluoro-3-methylquinazoline-2,4(1H,3H)-dione

tert-Butyl{1-[2-(7-fluoro-3-methyl-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 135) (200 mg, 0.476 mmol) was reacted as described forIntermediate 106. The crude trifluoro acetate of the title compound wasused without further purification for the next step (quantitative).

MS (ES): 321 (MH)⁺ for C₁₆H₂₁FN₄O₂

Intermediate 135: tert-Butyl{1-[2-(7-fluoro-3-methyl-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

7-Fluoro-3-methylquinazoline-2,4(1H,3H)-dione [Intermediate 136] (388mg, 2.0 mmol) was deprotonated with sodium hydride (100 mg, 60% in oil,2.4 mmol) and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) 2.75 mmol) as described for Intermediate 2.Chromatography on silica gel using ethyl acetate in hexanes (10-30%)gave the title compound as a yellow oil (200 mg, 24%).

MS (ES): 421 (MH)⁺ for C₂₁H₂₉FN₄O₄

¹H NMR (CDCl₂) δ: 1.2-1.3 (m, 2H); 1.43 (s, 9H); 1.44-1.5 (m, 1H);1.9-2.0 (m, 2); 2.15-2.35 (m, 2H); 2.65 (m, 2H); 2.85-3.0 (m, 1H); 3.45(s, 3H); 3.46-3.52 (m, 1H); 4.15-4.25 (m, 2H); 4.35-4.5 (m, 1H); 6.8-6.9(m, 1H); 6.91-7.0 (m, 1H); 8.2-8.26 (m, 1H).

Intermediate 136: 7-Fluoro-3-methylquinazoline-2,4(1H,3H)-dione

A suspension of sodium hydride (60% in mineral oil, 368 mg, 9.2 mmol) indimethylformamide (12 mL) was cooled to 0° C. and treated with2-amino-4-fluoro-N-methylbenzamide [Intermediate 137] (0.67 g, 4.0mmol). Phenyl chloroformate (0.6 mL, 0.73 g, 4.7 mmol) was added over 40minutes. After 1 hour a further portion of phenyl chloroformate (0.6 mL,0.73 g, 4.7 mmol) was added. The reaction was allowed to warm to roomtemperature and stir for two hours. The reaction was slowly added to 200mL of ice. The solid was filtered, washed with methanol to obtain theproduct (395 mg, 51%).

MS (ES): 193 (M-H)⁻ for C₉H₇FN₂O₂

¹H NMR (DMSO-d₆) δ: 3.23 (s, 3H); 6.89 (dd, 1H); 7.04 (td, 1H); 7.98(dd, 1H);

Intermediate 137: 2-Amino-4-fluoro-N-methylbenzamide

A mixture of 2-amino 4-fluoro benzoic acid (2.5 g, 16.13 mmol) and 1,3dimethyl urea (5.85 g, 66.5 mmol) was heated at 150° C. for 24 hours.The reaction was diluted with water, filtered and extracted twice withethyl acetate. The organic extracts were dried over magnesium sulfateand concentrated at reduced pressure. Chromatography on silica gel withethyl acetate in hexanes (0-50%) gave the title compound as a waxy solid(670 mg, 25%)

MS (ES): 169 (MH)⁺ for C₈H₉FN₂O

¹H NMR (DMSO-D6) δ: 2.69 (d, 3H); 6.29 (td, 1H); 6.43 (dd, 1H); 6.74 (s,2H); 7.49 (dd, 1H); 8.08-8.22 (m, 1H).

Example 677-Chloro-1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-1,8-naphthyridin-2(1H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-chloro-1,8-naphthyridin-2(1H)-onetrifluoroacetate (Intermediate 138, crude, 405 mg, 0.76 mmol),di-isopropyl ethylamine (0.38 mL, 2.27 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde [WO 2004/058144](180 mg, 1.1 mmol) and sodium cyanoborohydride (100 mg, 1.56 mmol) werereacted as described for Example 21. Chromatography on silica gel usingmethanol in dichloromethane (0-20% with 1% aqueous ammonium hydroxide)followed by reverse phase chromatography with 20-75%acetonitrile/water/10 mM NH₄OAc Buffer) gave the title compound (39 mg,11%).

MS (ES): 456 (MH)⁺ for C₂₃H₂₆ClN₅O₃

¹H NMR (CDCl₃) δ 1.32-1.43 (m, 2H); 1.87 (d, 2H); 2.10-2.21 (m, 2H);2.51-2.61 (m, 1H); 2.69 (t, 2H); 3.08 (d, 2H); 3.81 (s, 2H); 4.21-4.32(m, 4H); 4.58 (t, 2H); 6.68 (d, 1H); 6.78 (s, 1H); 7.11 (d, 1H); 7.58(d, 1H); 7.75 (d, 1H); 8.05 (s, 1H).

Intermediate 138:1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-chloro-1,8-naphthyridin-2(1H)-one

tert-Butyl{1-[2-(7-chloro-2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 139, 308 mg, 0.76 mmol) was reacted as described forIntermediate 106. The crude trifluoro acetate of the title compound wasused without further purification for the next step (quantitative).

Intermediate 139: tert-Butyl{1-[2-(7-chloro-2-oxo-1,8-naphthyridin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

A solution of 7-chloro-1,8-naphthyridin-2(1H)-one [J. Org. Chem. 1990,55, 4744-4750] in dry DMF (20 mL) (540 mg, 3.0 mmol) at 0° C. wastreated with sodium hydride (144 mg, 60% in mineral oil, 3.6 mmol). Thereaction mixture was allowed to warm to room temperature and stirred for1 hour. The reaction was cooled using an ice bath. A solution of2-{4-[(tert-butoxycarbonyl)amino]piperidin-1yl}ethyl methanesulfonate inDMF (Intermediate 6), 0.33 mmol/mL, 10 mL, 3.3 mmol) was then added over1 hour. The reaction was allowed to warm to room temperature and stirredovernight. The reaction mixture was diluted with water and extractedwith dichloromethane (3×50 mL). The combined organic layers were washedwith saturated sodium chloride solution (3×10 mL), dried over sodiumsulfate and evaporated. Chromatography on silica gel using methanol indichloromethane (0-15%) gave the title compound as a brown foam (711 mg,58%).

MS (ES): 407 (MH)⁺ for C₂₀H₂₇ClN₄O₃

¹H NMR (CDCl₃) δ 1.42 (s, 11H); 1.84-1.99 (m, 2H); 2.12-2.22 (m, 1H);2.22-2.37 (m, 2H); 2.66-2.80 (m, 2H); 3.03-3.19 (m, 1H); 3.39-3.55 (m,1H); 4.34-4.48 (m, 1H); 4.62 (t, 2H); 6.72 (d, 1H); 7.15 (d, 1H); 7.61(d, 1H); 7.78 (d, 1H).

Example 681-(2-{4-[2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxy-1,8-naphthyridin-2(1H)-one

A solution of7-chloro-1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-1,8-naphthyridin-2(1H)-one(Example 67) (95 mg, 0.21 mmol) in methanol (5 mL) was treated with asolution of sodium methoxide (0.5 M, 1 mL, 0.5 mmol). The reactionmixture was sealed in a tube and heated at 150 C for 1 hour usingmicrowave irradiation. The reaction mixture was concentrated at reducedpressure, partitioned between ethyl acetate and water. The aqueous layerwas extracted with ethyl acetate (3×10 mL) and chloroform/methanol (4:1)(3×15 mL). The combined organic extracts were dried over sodium sulfateand concentrated at reduced pressure. Chromatography on silica gel usingmethanol in dichloromethane (0-50%) gave the product as a colorlesssolid (29 mg, 31%)

MS (ES): 452 (MH)⁺ for C₂₄H₂₉N₅O₄

¹H NMR (CDCl₃) δ 1.39-1.54 (m, 2H); 1.90 (d, 2H); 2.13-2.28 (m, 2H);2.47-2.62 (m, 1H); 2.64-2.76 (m, 2H); 3.06 (d, 2H); 3.80 (s, 2H); 3.99(s, 3H); 4.26 (dd, 4H); 4.55-4.68 (m, 2H); 6.55 (dd, 2H); 6.80 (s, 1H)7.53 (d, 1H); 7.68 (d, 1H); 8.06 (s, 1H).

Example 691-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-fluoroquinoxalin-2(1H)-one

A mixture of1-[2-(4-aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one(Intermediate 140, 85 mg, 0.29 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(49 mg, 0.29 mmol) and molecular sieves 3 Å in dry methanol/chloroform(1:1, 10 mL) was heated to 70° C. for 3 hours. The reaction was allowedto cool to room temperature and sodium triacetoxy borohydride (190 mg,0.88 mmol) was added. After 30 minutes, the reaction was filteredthrough celite, the filtrate was concentrated to dryness, taken up in15% methanol/chloroform, and washed with saturated sodium bicarbonatesolution. The aqueous phase was reextracted twice with 15%methanol/chloroform. The combined organic phases were dried overmagnesium sulfate, filtered, and concentrated to dryness. Chromatographyon silica gel with 5% methanol in dichloromethane containing 0.25%ammonium hydroxide gave 70 mg (54%) of the title compound as anoff-white solid.

MS (ES): 440 (MN) for C₂₃H₂₆FN₅O₃

¹H NMR (DMSO-D6) δ 1.11-1.24 (m, 2H); 1.73 (d, 2H); 2.00 (t, 2H); 2.18(s, 1H); 2.25-2.38 (m, 1H); 2.51-2.56 (m, 2H); 2.87 (d, 2H); 3.64 (s,2H); 4.24-4.35 (m, 6H); 6.92 (s, 1H); 7.24 (td, 1H); 7.52 (dd, 1H); 7.87(dd, 1H); 7.99 (s, 1H); 8.18 (s, 1H).

Intermediate 140:1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one

A solution of tert-butyl{1-[2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 141, 240 mg, 0.62 mmol) in dichloromethane (20 mL) wastreated with trifluoroacetic acid (15 mL). After 45 minutes, thereaction was concentrated to dryness, the residue taken up inmethanol/chloroform (15:85, 30 mL) and washed with saturated sodiumbicarbonate solution. The aqueous layer was re-extracted withmethanol/chloroform (15:85, 3×30 mL. The combined organic phases weredried over magnesium sulfate and concentrated to dryness to give 170 mg(quantitative) of the crude product as an oil.

MS (ES): 291 (MW) for C₁₅H₁₉FN₄O

Intermediate 141: tert-Butyl{1-[2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

and

Intermediate 142: tert-Butyl{1-[2-(6-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4}carbamate

A suspension of a 1:1 mixture of 7-fluoroquinoxalin-2(1H)-one(Intermediate 143) and 6-fluoroquinoxalin-2(1H)-one (Intermediate 144)(1.5 g total, 9.1 mmol) was treated with sodium hydride (60% in oil,0.44 g, 11.0 mmol) at 0° C. The reaction was allowed to stir at roomtemperature for 2 hours. The reaction mixture was cooled to 0° C. and2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6, 1.33 mmol/mL, 11.0 mmol), dissolved in dry DMF (5 mL)was added and it was stirred at room temperature overnight. The reactionmixture was diluted with water and with diethyl ether (5×50 mL). Thecombined organic phases were dried over sodium sulfate and concentratedto dryness under reduced pressure. Chromatography with hexanes/acetone(5:1 to 3:1). The higher R_(f) material was isolated as a mixture ofIntermediate 141 with an O-alkylated isomer, which was rechromatographedon silica gel with hexanes/ethyl acetate (1:3) to give pure Intermediate141 as a colorless solid, 0.24 g, 14%. Isolation of the lower R_(f)material from the first column gave 0.38 g (21%) of pure Intermediate142 as a colorless solid.

Intermediate 141

MS (ES): 391 (MH⁺) for C₂₀H₂₇FN₄O₃

¹H NMR (DMSO-D6) δ 1.25-1.38 (m, 11H); 1.56-1.68 (m, 2H); 2.01 (t, 2H);2.50-2.56 (m, 2H); 2.82-2.93 (m, 2H); 3.16 (s, 1H); 4.27 (t, 2H); 6.72(d, 1H); 7.23 (t, 1H); 7.50 (d, 1H); 7.83-7.91 (m, 1H); 8.17 (s, 1H).

Intermediate 142

MS (ES): 391 (MW) for C₂₀H₂₇FN₄O₃

¹H NMR (DMSO-D6) δ 1.24-1.38 (m, 11H); 1.65 (d, 2H); 2.03 (t, 2H);2.51-2.58 (m, 2H); 2.88 (d, 2H); 3.11-3.26 (m, 1H); 4.31 (t, 2H); 6.75(d, 1H); 7.57 (d, 1H); 7.63-7.71 (m, 2H); 8.29 (s, 1H).

Intermediate 143: 7-Fluoroquinoxalin-2(1H)-one

and

Intermediate 144: 6-Fluoroquinoxalin-2(1H)-one

A mixture of 4-fluorobenzene-1,2-diamine (5.0 g, 39.7 mmol) and ethyloxoacetate (50 wt % in toluene, 17 mL, 79.4 mmol) in ethanol (100 mL)was stirred for two hours at room temperature. The precipitate wascollected by filtration, washed with ethanol, and dried under vacuumgiving 4.5 g of a solid. ¹H NMR revealed a 1:1 mixture of Intermediates143 and 144. This mixture was used for the next step.

MS (ES): 165 (MH⁺) for C₈H₅FN₂O

Example 706-[({1-[2-(7-Fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one(Intermediate 140, 85 mg crude, 0.29 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (52 mg, 0.29 mmol) and sodium triacetoxy borohydride (190mg, 0.88 mmol) were reacted as described according to Example 69 to give90 mg (69%) of the free base of the product.

MS (ES): 453 (MH⁺) for C₂₃H₂₅FN₆O₃

¹H NMR (DMSO-D6) δ 1.12-1.26 (m, 2H); 1.69-1.81 (m, 2H); 2.01 (t, 2H);2.27-2.42 (m, 1H); 2.51-2.60 (m, 2H); 2.88 (d, 2H); 3.67 (s, 2H); 4.28(t, 2H); 4.60 (s, 2H); 7.00 (d, 1H); 7.20-7.31 (m, 2H); 7.52 (dd, 1H);7.88 (dd, 1H); 8.19 (s, 1H); 11.16 (s, 1H).

Example 711-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-fluoroquinoxalin-2(1H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-6-fluoroquinoxalin-2(1H)-one(Intermediate 145, 87 mg, 0.30 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(50 mg, 0.30 mmol), and sodium triacetoxy borohydride (200 mg, 0.90mmol) were reacted as described for Example 69 to give the free base ofthe title compound as an oil. The free base was taken up in isopropanol(10 mL) and treated with 2.0M HCl in ether (3 eq). Solvent was removedunder reduced pressure. The resulting solid was triturated withdichloromethane/hexanes (2 mL/10 mL). The precipitate was collected byfiltration to give 45 mg (29%) of the bis-hydrochloride salt of theproduct.

MS (ES): 440 (MH⁺) for C₂₃H₂₆FN₅O₃

¹H NMR (D₂O) δ 1.83-2.06 (m, 2H); 2.42 (d, 2H); 3.17 (t, 2H); 3.48-3.68(m, 3H); 3.79-4.01 (m, 2H); 4.30-4.41 (m, 4H); 4.43-4.51 (m, 2H);4.65-4.70 (m, 2H); 7.27-7.30 (m, 1H); 7.44-7.55 (m, 2H); 7.59 (dd, 1H);8.20-8.25 (m, 2H).

Intermediate 145:1-[2-(4-Aminopiperidin-1-yl)ethyl]-6-fluoroquinoxalin-2(1H)-one

tert-Butyl{1-[2-(6-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 142, 380 mg, 0.97 mmol) was reacted with trifluoroaceticacid in dichloromethane as described for Intermediate 140 to give 260 mg(93%) of the crude product as an oil.

MS (ES): 291 (MH⁺) for C₁₅H₁₉FN₄O

Example 721-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxyquinoxalin-2(1H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxyquinoxalin-2(1H)-one(Intermediate 146, 60 mg crude, 0.20 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(33 mg, 0.20 mmol), and sodium triacetoxy borohydride (130 mg, 0.60mmol) were reacted as described for Example 69 to give the free base ofthe title compound as an oil. The free base was taken up in isopropanoland treated with 4.0M HCl in dioxane (3 eq). Solvent was removed underreduced pressure to give 28 mg (27% yield) of the bis-hydrochloride saltof the product.

MS (ES): 452 (MH⁺) for C₂₄H₂₉N₅O₄

¹H NMR (D₂O) δ 1.86-2.02 (m, 2H); 2.36-2.49 (m, 2H); 3.09-3.23 (m, 2H);3.52 (t, 2H); 3.56-3.68 (m, 1H); 3.82-3.95 (m, 5H); 4.32-4.40 (m, 4H);4.43-4.50 (m, 2H); 4.61 (t, 2H); 6.82 (d, 1H); 7.03 (dd, 1H); 7.29 (s,1H); 7.71 (d, 1H); 7.97 (s, 1H); 8.22 (s, 1H).

Intermediate 146:1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxyquinoxalin-2(1H)-one

tert-Butyl{1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 147, 190 mg, 0.47 mmol) was reacted with trifluoroaceticacid in dichloromethane as described for Intermediate 140 to give 110 mgof the crude product as an oil.

MS (ES): 303 (MH⁺) for C₁₆H₂₂N₄O₂

Intermediate 147: tert-Butyl1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl) carbamate

7-methoxyquinoxalin-2(1H)-one (Intermediate 148, 300 mg, 1.70 mmol) wasdeprotonated with sodium hydride (100 mg, 60% in oil, 2.56 mmol) andalkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethylmethanesulfonate (Intermediate 6) (3.4 mmol) as described forIntermediate 2. Chromatography on silica gel with 25% acetone in hexanesgave 200 mg (29%) of the product as a colorless solid.

MS (ES): 403 (MH⁺) for C₂₁H₃₀N₄O₄

¹H NMR (DMSO-D6) δ 1.26-1.40 (m, 11H); 1.57-1.72 (m, 2H); 1.97-2.11 (m,2H); 2.51-2.61 (m, 2H); 2.85-2.98 (m, 2H); 3.19 (s, 1H); 3.92 (s, 3H);4.32 (t, 2H); 6.76 (d, 1H); 6.95-7.04 (m, 2H); 7.70-7.78 (m, 1H); 8.04(s, 1H).

Intermediate 148: 7-Methoxyquinoxalin-2(1H)-one

A suspension of 2-chloro-7-methoxyquinoxaline (Intermediate 149, 720 mg,3.70 mmol) in 5M HCl (25 mL) was heated to 110° C. for 1 hour. Thereaction was cooled to room temperature and let stand for 24 hours. Theresulting precipitate was collected by filtration. A second crop ofmaterial was collected after concentration the mother liquor. The twocrops were combined and crystallized from methanol to give 550 mg (85%)of the product as an off-white solid.

MS (ES): 177 (MH⁺) for C₉H₈N₂O₂

¹H NMR (DMSO-D6) δ 3.83 (s, 3H); 6.76 (d, 1H); 6.91 (dd, 1H); 7.69 (d,1H); 7.94-8.00 (m, 1H); 12.32 (s, 1H).

Intermediate 149: 2-Chloro-7-methoxyquinoxaline

A solution of 4-methoxybenzene-1,2-diamine (16.8 g, 0.12 mmol) inethanol (250 mL) was treated with a solution of ethyl oxoacetate (50 wt% in toluene, 50 mL, 0.23 mmol) dropwise with cooling in an ice bath.The reaction was allowed to warm to room temperature and after 2 hours,a precipitate was collected by filtration giving 15 g of a brown solidas a 2:1 mixture of 6-methoxyquinoxalin-2(1H)-one to7-methoxyquinoxalin-2(1H)-one. These isomers were inseparable by TLC.The mixture was suspended in phosphorus oxychloride (150 mL) and heatedto reflux for 1 hour. The reaction was cooled to room temperature andwas quenched on ice. The pH of the mixture was adjusted to pH 8 withsolid sodium carbonate, it was extracted with ethyl acetate, washed withbrine, dried over sodium sulfate, filtered, and concentrated to drynessto give 10.4 g of a crude mixture of 2-chloro-6-methoxyquinoxaline andthe desired 2-chloro-7-methoxyquinoxaline. Chromatography on silica gelwith 5% ethyl acetate in hexanes afforded 0.77 g of the product as acolorless solid.

MS (ES): 195 (MH⁺) for C₉H₇ClN₂O

¹H NMR (CDCl₃) δ 3.96 (s, 3H); 7.29 (d, 1H); 7.41 (dd, 1H); 7.97 (d,1H); 8.63 (s, 1H).

Example 736-[({1-[2-(7-Methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxyquinoxalin-2(1H)-one(Intermediate 146, 60 mg crude, 0.20 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (36 mg, 0.20 mmol), and sodium triacetoxy borohydride (130mg, 0.60 mmol) were reacted as described according to Example 69 to givethe free base of the product, which was crystallized fromdichloromethane/ethyl acetate to give 45 mg (50%) as a colorless solid.

MS (ES): 465 (MH⁺) for C₂₄H₂₈N₆O₄

¹H NMR (DMSO-D6) δ 1.06-1.39 (m, 2H); 1.66-1.87 (m, 2H); 2.04 (t, 2H);2.33-2.49 (m, 1H); 2.56 (t, 2H); 2.92 (d, 2H); 3.70 (s, 2H); 3.92 (s,3H); 4.32 (t, 2); 4.61 (s, 2H); 6.86-7.09 (m, 3H); 7.30 (d, 1H); 7.75(d, 1H); 8.04 (s, 1H); 11.18 (s, 1H).

Example 746-[({1-[2-(7-Methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]thiazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxyquinoxalin-2(1H)-one(Intermediate 146, 250 mg crude, 0.83 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (WO2004/058144) (160 mg, 0.83 mmol), and sodium triacetoxy borohydride (530mg, 2.50 mmol) were reacted as described according to Example 69.Chromatography on silica gel with 10% methanol in dichloromethanecontaining 0.25% ammonium hydroxide afforded the free base of theproduct. This was triturated with dichloromethane and the precipitatewas collected by filtration giving 230 mg (58%) of the title compound asa colorless solid.

MS (ES): 481 (MH⁺) for C₂₄H₂₈N₆O₃S

¹H NMR (DMSO-D6) δ 1.27 (s, 2H); 1.69-1.90 (m, 2H); 2.04 (t, 2H);2.39-2.48 (m, 1H); 2.56 (t, 2H); 2.93 (d, 2H); 3.53 (s, 2H); 3.75 (s,2H); 3.92 (s, 3H); 4.33 (t, 2H); 6.91-7.05 (m, 2H); 7.10 (d, 1H);7.67-7.83 (m, 2H); 8.04 (s, 1H); 10.88 (s, 1H).

Example 751-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6,7-difluoroquinoxalin-2(1H)-one

1-[2-(4-Aminopiperidin-2-yl)ethyl]-6,7-difluoroquinoxalin-2(1H)-one(Intermediate 150, 190 mg, 0.62 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(100 mg, 0.62 mmol), and sodium triacetoxy borohydride (390 mg, 1.90mmol) were reacted as described according to Example 69. Chromatographyon silica gel with 10% methanol in dichloromethane containing 0.25%ammonium hydroxide gave the free base of the product as an oil. The freebase was taken up in dichloromethane (2 mL) and diluted with diethylether (10 mL). A solution of HCl in diethyl ether (2M, 2.2 eq) wasadded. The resulting precipitate was collected by filtration to give 180mg (55%) of the bis-hydrochloride salt of the product.

MS (ES): 458 (MH⁺) for C₂₃H₂₅F₂N₅O₃

¹H NMR (D₂O) δ 1.82-2.06 (m, 2H); 2.40 (d, 2H); 3.16 (t, 2H); 3.48-3.68(m, 3H); 3.89 (d, 2H); 4.27-4.38 (m, 4H); 4.39-4.49 (m, 2H); 4.63 (t,2H); 7.15-7.28 (m, 1H); 7.44-7.61 (m, 1H); 7.69-7.85 (m, 1H); 8.10-8.28(m, 2H).

Intermediate 150:1-[2-(4-Aminopiperidin-1-yl)ethyl]-6,7-difluoroquinoxalin-2(1H)-one

tert-Butyl{1-[2-(6,7-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 151, 500 mg, 1.23 mmol) was reacted with trifluoroaceticacid in dichloromethane as described for Intermediate 140 to give 380 mg(quantitative) of the crude product as an oil.

MS (ES): 309 (MH⁺) for C₁₅H₁₈F₂N₄O

Intermediate 151: tert-Butyl{1-[2-(6,7-difluoro-2-oxoquinoxalin-1-(2)-yl)ethyl]piperidin-4-yl}carbamate

6,7-Difluoroquinoxalin-2(1H)-one (Intermediate 152, 1.0 g, 5.50 mmol)was deprotonated with sodium hydride (60% in oil, 0.26 g, 6.60 mmol) andalkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethylmethanesulfonate (Intermediate 6) (6.6 mmol) as described forIntermediate 2. Chromatography on silica gel with 5% toluene/ethylacetate gave 500 mg (23%) of the product as a colorless solid.

MS (ES): 409 (MH⁺) for C₂₀H₂₆F₂N₄O₃

¹H NMR (DMSO-D6) δ 1.10-1.45 (m, 11H); 1.54-1.75 (m, 2H); 1.90-2.13 (m,2H); 2.52-2.59 (m, 2H); 2.86 (d, 2H); 3.16 (s, 1H); 4.28 (t, 2H); 6.75(d, 1H); 7.81 (dd, 1H); 7.96 (dd, 1H); 8.25 (s, 1H).

Intermediate 152: 6,7-Difluoroquinoxalin-2(1H)-one

To a stirred solution of 4,5-difluorobenzene-1,2-diamine (4.7 g, 32.6mmol) in ethanol (75 mL) was added ethyl oxoacetate (50 wt % in toluene,13.3 mL, 65.3 mmol). The reaction was stirred at room temperatureovernight. The resulting precipitate was collected by filtration, washedwith ethanol, and dried under reduced pressure to give 4.3 g (73%) ofthe product as a colorless solid.

MS (ES): 183 (MH⁺) for C₈H₄F₂N₂O

¹H NMR (DMSO-D6) δ 7.23 (dd, 1H); 7.93 (dd, 1H); 8.19 (s, 1H); 12.54 (s,1H).

Example 76 6-[({1-[2-(6,7-Difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-6,7-difluoroquinoxalin-2(1H)-one(Intermediate 150, 190 mg, 0.62 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (110 mg, 0.62 mmol), and sodium triacetoxy borohydride (390mg, 1.90 mmol) were reacted as described according to Example 69 to give180 mg (62%) of the free base of the product as a colorless solid.

MS (ES): 471 (MH⁺) for C₂₃H₂₄F₂N₆O₃

¹H NMR (DMSO-D6) δ 1.12-1.26 (m, 2H); 1.69-1.83 (m, 2H); 2.01 (t, 2H);2.42 (s, 1H); 2.53 (t, 2H); 2.88 (d, 2H); 3.69 (s, 2H); 4.29 (t, 2H);4.60 (s, 2H); 7.01 (d, 1H); 7.30 (d, 1H); 7.82 (dd, 1H); 7.97 (dd, 1H);8.25 (s, 1H); 11.18 (s, 1H).

Example 771-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7,8-difluoroquinoxalin-2(1H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7,8-difluoroquinoxalin-2(1H)-one(Intermediate 153, 130 mg, 0.42 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(70 mg, 0.42 mmol), and sodium triacetoxy borohydride (270 mg, 1.30mmol) were reacted as described according to Example 71 to give 35 mg(16%) of the bis-hydrochloride salt of the product as a colorless solid.

MS (ES): 458 (MH⁺) for C₂₃H₂₅F₂N₅O₃

¹H NMR (D₂O) δ 1.89-2.02 (m, 2H); 2.43 (d, 2H); 3.18 (t, 2H); 3.52-3.64(m, 3H); 3.88 (d, 2H); 4.29-4.34 (m, 4H); 4.38-4.43 (m, 2H); 4.71-4.77(m, 2H); 7.17 (s, 1H); 7.27-7.38 (m, 1H); 7.62-7.69 (m, 1H); 8.15 (s,2H).

Intermediate 153:1-[2-(4-Aminopiperidin-1-yl)ethyl]-7,8-difluoroquinoxalin-2(1H)-one

tert-Butyl{1-[2-(7,8-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 154, 320 mg, 0.78 mmol) was reacted with trifluoroaceticacid in dichloromethane as described for Intermediate 140 to give 240 mg(quantitative) of the crude product as an oil.

MS (ES): 309 (MH⁺) for C₁₅H₁₈F₂N₄O

Intermediate 154: tert-Butyl{1-[2-(7,8-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

7,8-Difluoroquinoxalin-2(1H)-one (Intermediate 155—a mixture ofregioisomers containing 30% 5,6-difluoroquinoxalin-2(1H)-one, 1.0 g,5.50 mmol) was deprotonated with sodium hydride (60% in oil, 0.26 g,6.60 mmol) and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (6.6 mmol) as described for Intermediate 2.Chromatography on silica gel with 70-100% ethyl acetate in hexanes gave320 mg of the product as a colorless solid.

MS (ES): 409 (MH⁺) for C₂₀H₂₆F₂N₄O₃

¹H NMR (DMSO-D6) δ 1.30 (d, 2H); 1.37 (s, 9H); 1.64 (d, 2H); 2.07 (t,2H); 2.59 (t, 2H); 2.81 (d, 2H); 3.20 (s, 1H); 4.36 (t, 2H); 6.76 (d,1H); 7.48 (td, 1H); 7.72 (ddd, 1H); 8.23 (s, 1H).

Intermediate 155: 7,8-Difluoroquinoxalin-2(1H)-one

3,4-Difluorobenzene-1,2-diamine (4.6 g, 31.6 mmol) and ethyl oxoacetate(50 wt % in toluene, 13.0 mL, 63.2 mmol) were reacted as described forIntermediate 152 to give 3.7 g of product as an off white solid, mixturewith 30% of the regioisomer 5,6-difluoroquinoxalin-2(1H)-one. Themixture was carried on to the next step.

MS (ES): 183 (MH⁺) for C₈H₄F₂N₂O

Example 786-[({1-[2-(7,8-Difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7,8-difluoroquinoxalin-2(1H)-one(Intermediate 153, 130 mg, 0.42 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (70 mg, 0.42 mmol), and sodium triacetoxy borohydride (270mg, 1.30 mmol) were reacted as described for Example 69 to give 82 mg(41%) of the free base of the product.

MS (ES): 471 (MH⁺) for C₂₃H₂₄F₂N₆O₃

1H NMR (DMSO-D6) δ 1.07-1.22 (m, 2H); 1.69 (d, 2H); 1.98 (t, 2H); 2.35(s, 1H); 2.52 (t, 2H); 2.76 (d, 2H); 3.63 (s, 2H); 4.30 (t, 2H); 4.54(s, 2H); 6.95 (d, 1H); 7.24 (d, 1H); 7.35-7.47 (m, 1H); 7.61-7.71 (m,1H); 8.17 (s, 1H); 11.12 (s, 1H).

Example 79 6-[({1-[2-(6,7-Dimethoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-6,7-dimethoxyquinoxalin-2 (1H)-one(Intermediate 156, 75 mg, 0.23 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (40 mg, 0.23 mmol), and sodium triacetoxy borohydride (150mg, 0.69 mmol) were reacted as described according to Example 69 to give78 mg (68%) of the free base of the product as a colorless solid.

MS (ES): 495 (MH⁺) for C₂₅H₃₀N₆O₅

¹H NMR (DMSO-D6) δ 1.06-1.38 (m, 2H); 1.65-1.85 (m, 2H); 1.95-2.13 (m,2H); 2.29-2.42 (m, 1H); 2.51-2.64 (m, 2H); 2.92 (d, 2H); 3.67 (s, 2H);3.85 (s, 3H); 3.88-4.04 (m, 3H); 4.24-4.45 (m, 2H); 4.52-4.66 (m, 2H);6.94-7.09 (m, 2H); 7.21-7.37 (m, 2); 7.98-8.11 (m, 1H); 11.06-11.23 (m,1H).

Intermediate 156:1-[2-(4Aminopiperidin-1-yl)ethyl]-6,7-dimethoxyquinoxalin-2(1H)-one

tert-Butyl{1-[2-(6,7-dimethoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 157, 100 mg, 0.23 mmol) was reacted with trifluoroaceticacid in dichloromethane as described for Intermediate 140 to give 75 mg(quantitative) of the crude product as an oil.

MS (ES): 333 (MH⁺) for C₁₇H₂₄N₄O₃

Intermediate 157: tert-Butyl{1-[2-(6,7-dimethoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

6,7-Dimethoxyquinoxalin-2(1H)-one (Intermediate 158, 540 mg, 2.60 mmol)was deprotonated with sodium hydride (60% in oil, 2.90 mmol) andalkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethylmethanesulfonate (Intermediate 6) (3.9 mmol) as described forIntermediate 2. Chromatography on silica gel with 20-50% acetone inhexanes gave 310 mg (28%) of the product as an off-white solid.

MS (ES): 433 (MH⁺) for C₂₂H₃₂N₄O₅

¹H NMR (DMSO-D6) δ 1.25-1.39 (m, 11H); 1.63 (d, 2H); 1.98-2.12 (m, 2H);2.57 (t, 2H); 2.92 (d, 2H); 3.19 (s, 1H); 3.84 (s, 3H); 3.95 (s, 3H);4.35 (t, 2H); 6.75 (d, 1H); 7.04 (s, 1H); 7.31 (s, 1H); 8.05 (s, 1H).

Intermediate 158: 6,7-Dimethoxyquinoxalin-2(1H)-one

A mixture of 1,2-dimethoxy-4,5-dinitrobenzene (5.7 g, 25.0 mmol) inethanol/acetic acid (140 mL, 1:1) was hydrogenated over palladium oncarbon (10%, 1 g) at normal pressure and room temperature for 3 hours,then filtered through a pad of celite. The filtrate containing the crudediamine was treated with ethyl oxoacetate (50 wt % in toluene, 10 mL, 50mmol) and the reaction was stirred at room temperature overnight. Theresulting precipitate was collected by filtration. This material wassuspended in a mixture of methanol/dichloromethane and solvent wasremoved under reduced pressure to remove traces of acetic acid to give2.0 g (38%) of product as a solid.

MS (ES): 207 (MH⁺) for C₁₀H₁₀N₂O₃

¹H NMR (DMSO-D6) δ 3.81-3.83 (m, 3H); 3.83-3.85 (m, 3H); 6.78-6.81 (m,1H); 7.25-7.27 (m, 1H); 7.97-8.01 (m, 1H); 12.26-12.34 (m, 1H).

Example 806-[({1-[2-(7-Methoxy-3-methyl-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxy-3-methylquinoxalin-2(1H)-one(Intermediate 159, 75 mg, 0.24 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (42 mg, 0.24 mmol), and sodium triacetoxy borohydride (150mg, 0.72 mmol) were reacted as described according to Example 69 to give80 mg (73% yield) of the free base of the product.

MS (ES): 479 (MH⁺) for C₂₅H₃₀N₆O₄

¹H NMR (DMSO-D6) δ 1.23 (q, 2H); 1.77 (d, 2H); 2.04 (t, 2H); 2.31-2.45(m, 4H); 2.51-2.61 (m, 2H); 2.91 (d, 2H); 3.68 (s, 2H); 3.89 (s, 3H);4.31 (t, 2H); 6.85-7.10 (m, 3H); 7.29 (d, 1H); 7.59-7.73 (m, 1H); 11.17(s, 1H).

Intermediate 159:1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-methoxy-3-methylquinoxalin-2(1H)-one

tert-Butyl{1-[2-(7-methoxy-3-methyl-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 160, 100 mg, 0.24 mmol) was reacted with trifluoroaceticacid in dichloromethane as described for Intermediate 140 to give 75 mg(99% yield) of the crude product as an oil.

MS (ES): 317 (MH⁺) for C₁₇H₂₄N₄O₂

Intermediate 160: tert-Butyl{1-[2-(7-methoxy-3-methyl-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

7-Methoxy-3-methylquinoxalin-2(1H)-one (Intermediate 161, 500 mg, 2.60mmol) was deprotonated with sodium hydride (60% in oil, 2.90 mmol) andalkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethylmethanesulfonate (Intermediate 6) (3.9 mmol) as described forIntermediate 2. Chromatography on silica gel with 70% ethyl acetate inhexanes, followed by a second chromatography on silica gel with 20%acetone in hexanes gave 110 mg (10%) of the product as a colorlesssolid.

MS (ES): 417 (WO for C₂₂H₃₂N₄O₄

¹H NMR (DMSO-D6) δ 1.21-1.46 (m, 11H); 1.65 (d, 2H); 2.05 (t, 2H); 2.38(s, 3H); 2.51-2.59 (m, 2H); 2.92 (d, 2H); 3.18 (s, 1H); 3.90 (s, 3H);4.31 (t, 2H); 6.77 (d, 1H); 6.91-7.00 (m, 2H); 7.58-7.73 (m, 1H).

Intermediate 161: 7-Methoxy-3-methylquinoxalin-2(1H)-one

A suspension of 3-chloro-6-methoxy-2-methylquinoxaline (Intermediate162, 1.5 g, 7.21 mmol) in 5M HCl (30 mL) was heated to 110° C. for 1hour. The reaction mixture was neutralized with saturated sodiumcarbonate solution, diluted with water and extracted with ethyl acetate(3 times). The combined organic phases were dried over magnesium sulfateand concentrated to a small volume under reduced pressure. Theprecipitate was collected by filtration to give 1.0 g (71%) of productas an off-white solid.

MS (ES): 191 (MH⁺) for C₁₀H₁₀N₂O₂

¹H NMR (DMSO-D6) δ 2.34 (s, 3H); 3.80 (s, 3H); 6.73 (d, 1H); 6.83-6.89(m, 1H); 7.59 (d, 1H); 12.19 (s, 1H).

Intermediate 162: 3-Chloro-6-methoxy-2-methylquinoxaline

A suspension of 4-methoxybenzene-1,2-diamine (5.0 g, 36.2 mmol) in water(100 mL) was heated under sonication for 5 minutes. 2-Oxopropanoic acid(2.5 mL, 36.2 mmol) was added and it was stirred for 2 hours. Theprecipitate was collected by filtration and dried under vacuum andheating, over phosphorus pentoxide, to give 3.0 g of a mixture of theproduct together with 6-methoxy-3-methylquinoxalin-2(1H)-one. Thismixture was suspended in phosphorus oxychloride (30 mL) and heated to115° C. for 30 min. The mixture was quenched on ice and neutralized withsolid sodium carbonate. The aqueous mixture was extracted with ethylacetate (4 times). The combined organic phases were dried over magnesiumsulfate, filtered, and concentrated to dryness under reduced pressure.Chromatography on silica gel with 5% ethyl acetate in hexanes andisolation of the higher migrating regioisomer gave 0.9 g of product asan off-white solid.

MS (ES): 209 (MH⁺) for C₁₀H₉ClN₂O

¹H NMR (DMSO-D6) δ 2.71 (s, 3H); 3.93 (s, 3H); 7.39 (d, 1H); 7.49 (dd,1H); 7.95 (d, 1H).

Example 811-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-2(1H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]quinolin-2(1H)-one (Intermediate 163,170 mg crude, 0.63 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(100 mg, 0.63 mmol), and sodium triacetoxy borohydride (400 mg, 1.90mmol) were reacted as described according to Example 69 to give the freebase of the product as an oil. The free base was taken up indichloromethane (2 mL) and ethanol (8 mL) and treated with a solution of4M HCl/dioxane (2 eq). The resulting precipitate was collected byfiltration to give 188 mg (60%) of the bis-hydrochloride salt of theproduct as a colorless solid.

MS (ES): 421 (MH⁺) for C₂₄H₂₈N₄O₃

¹H NMR (D₂O) δ 1.86-2.06 (m, 2H); 2.36-2.54 (m, 2H); 3.06-3.27 (m, 2H);3.46-3.70 (m, 3H); 3.89 (d, 2H); 4.29-4.42 (m, 4H); 4.42-4.53 (m, 2H);4.65-4.70, (m, 2H); 6.66 (d, 1H); 7.29 (s, 1H); 7.34 (t, 1H); 7.47 (d,1H); 7.59-7.78 (m, 2H); 7.95 (d, 1H); 8.22 (s, 1H).

Intermediate 163: 1-[2-(4-Aminopiperidin-1-yl)ethyl]quinolin-2(1H)-one

To a solution of tert-butyl{1-[2-(2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 164, 220 mg, 0.59 mmol) in dioxane (5 mL) was added asolution of HCl in dioxane (4M, 9 mL), followed by water (1 mL) and itwas stirred at room temperature over night. An addition 5 mL ofHCl/dioxane was added to the reaction. After 1 hr, the reaction wasconcentrated to dryness. The crude product was partitioned between 10%methanol/dichloromethane (50 mL) and 1M sodium hydroxide (50 mL). Theaqueous phase was back extracted with 10% methanol/dichloromethane (50mL) and the combined organic phases were washed with brine, dried oversodium sulfate and concentrated under reduced pressure to give 170 mg(quantitative) of the crude product as an oil.

MS (ES): 272 (MH⁺) for C₁₆H₂₁N₃O

Intermediate 164: tert-Butyl{1-[2-(2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

Quinolin-2(1H)-one (250 mg, 1.7 mmol) was deprotonated with sodiumhydride (60% in oil, 70 mg, 1.7 mmol) and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (1.7 mmol) as described for Intermediate 141.Chromatography on silica gel with 0-5% methanol in dichloromethane gave220 mg (35%) of product as a colorless solid.

MS (ES): 372 (MH⁺) for C₂₁H₂₉N₃O₃

Example 821-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-4(1H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]quinolin-4(1H)-one (Intermediate 165,180 mg crude, 0.66 mmol),2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(110 mg, 0.66 mmol), and sodium triacetoxy borohydride (420 mg, 2.0mmol) were reacted as described according to Example 81 to give thebis-hydrochloride salt of the product 53 mg (16%) as a colorless solid.

MS (ES): 421 (MH⁺) for C₂₄H₂₈N₄O₃

¹H NMR (D₂O) δ 1.90-2.13 (m, 2H); 2.44 (d, 2H); 3.22 (t, 2H); 3.58-3.70(m, 3H); 3.77 (d, 2H); 4.33-4.40 (m, 2H); 4.42 (s, 2H); 4.46-4.53 (m,2H); 4.75-4.86 (m, 2H); 6.47 (d, 1H); 7.36 (s, 1H); 7.51 (t, 1H); 7.68(d, 1H); 7.77-7.89 (m, 1H); 8.11-8.21 (m, 2H); 8.25 (s, 1H).

Intermediate 165: 1-[2-(4-Aminopiperidin-1-yl)ethyl]quinolin-4(1H)-onetert-Butyl {1-[2-(4-oxoquinolin-1(4H)-yl)ethyl]piperidin-4-yl}carbamate

(Intermediate 166, 480 mg crude, 1.29 mmol) was reacted with 4MHCl/dioxane in dioxane as described for Intermediate 163 to give 180 mg(51%) of the crude product as an oil.

MS (ES): 272 (MH⁺) for C₁₆H₂₁N₃O

Intermediate 166: tert-Butyl{1-[2-(4-oxoquinolin-1(4H)-yl)ethyl]piperidin-4-yl}carbamate

Quinolin-4(1H)-one (250 mg, 1.7 mmol) was deprotonated with sodiumhydride (60% in oil, 70 mg, 1.7 mmol) and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (1.7 mmol) as described for Intermediate 141. Theprecipitate formed in the reaction mixture was collected by filtrationto give 480 mg (76%) of product as a colorless solid.

MS (ES): 372 (MH⁺) for C₂₁H₂₉N₃O₃

Example 83Cis(±)6-[({1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]-3-methoxypiperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

Cis(±)1-[2-(4-amino-3-methoxypiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one(Intermediate 167, 140 mg, 0.42 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (75 mg, 0.42 mmol) and sodium triacetoxy borohydride (250mg, 1.20 mmol) were reacted as described according to Example 69.Chromatography on silica gel with 5% methanol in dichloromethanecontaining 0.50% ammonium hydroxide gave 120 mg (57%) of the free baseof the product.

MS (ES): 500 (MH⁺) for C₂₅H₂₇F₂N₅O₄

¹H NMR (CDCl₃) δ 1.66-1.87 (m, 2H); 2.22-2.44 (m, 2H); 2.55-2.83 (m,3H); 2.93 (d, 1H); 3.14 (d, 1H); 3.34-3.45 (m, 3H); 3.47-3.56 (m, 1H);3.80-3.86 (m, 2H); 4.25-4.59 (m, 2H); 4.63 (s, 2H); 6.65 (d, 1H);6.67-6.77 (m, 1H); 6.99 (t, 2H); 7.21 (d, 1H); 7.88 (d, 1H);

Intermediate 167:Cis(±)1-[2-(4-amino-3-methoxypiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one

Cis(±)1-{2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one(Intermediate 168, 240 mg, 0.46 mmol) was hydrogenated inmethanol/acetonitrile (10 mL, 9:1) over palladium hydroxide on carbon(20%, 120 mg) at room temperature and normal pressure for 4 hours. Thereaction mixture was filtered through celite and the filtrate wasconcentrated to dryness under reduced pressure to give 140 mg (90%) ofcrude product. This was used without further purification.

MS (ES): 338 (MH⁺) for C₁₇H₂₁F₂N₃O₂

Intermediate 168:Cis(±)1-{2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one

A solution of 5,7-difluoroquinolin-2(1H)-one (Intermediate 25, 300 mg,1.70 mmol) in dry DMF (10 mL) was treated with sodium hydride (60% inoil, 80 mg, 2.00 mmol) with cooling in an ice bath. The reaction wasstirred at room temperature for 90 min. The reaction was again cooled inan ice bath and treated with a solution ofcis(±)2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethylmethanesulfonate in dry DMF (10 mL) (Intermediate 169, 1.2 eq, 2.00mmol). The reaction was stirred at room temperature overnight. It wasquenched with a small amount of water and concentrated to dryness.Residual DMF was removed by co-evaporating with toluene and the residuewas partitioned between ethyl acetate (50 mL) and water (20 mL). Thebiphasic mixture was filtered, the phases separated and the aqueousphase was back extracted two times with ethyl acetate (2×50 mL). Thecombined organic phases were dried over magnesium sulfate, filtered, andconcentrated to dryness. Chromatography on silica gel with a gradient of10-20% acetone in hexanes gave 240 mg (27%) of product as a colorlesssolid.

MS (ES): 518 (MH⁺) for C₃₁H₃₃F₂N₃O₂

¹H NMR (DMSO-D6) δ 1.49-1.60 (m, 1H); 1.70-1.84 (m, 1H); 1.92-2.06 (m,2H); 2.37-2.47 (m, 2H); 2.99-3.12 (m, 1H); 3.16-3.22 (m, 1H); 3.25 (s,3H); 3.30-3.40 (m, 1H); 3.56 (s, 1H); 3.59-3.86 (m, 4H); 4.28 (t, 2H);6.62 (d, 1H); 7.15-7.24 (m, 3H); 7.24-7.41 (m, 9H); 7.96 (d, 1H).

Intermediate 169:Cis(±)2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethylmethanesulfonate

Cis(±)2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethanol (Intermediate170, 740 mg, 2.1 mmol) was reacted with methanesulfonyl chloride (0.20mL, 2.5 mmol) in the presence of triethylamine (0.41 mL, 2.9 mmol) asdescribed for Intermediate 6. The crude product was presumed to beunstable and was used without further purification directly for the nextstep.

Intermediate 170:Cis(±)2-[4-(dibenzylamino)-3-methoxypiperidin-1-yl]ethanol

A mixture of cis(±)N,N-dibenzyl-3-methoxypiperidin-4-amine (1.7 g, 5.5mmol) (WO 2005/068461), bromoethanol (0.5 mL, 7.1 mmol), andN,N-diisopropylethylamine (1.4 mL, 8.3 mmol) were reacted as describedfor Intermediate 37, but heating for one hour at 70° C. Chromatographyon silica gel with 5% methanol in dichloromethane containing 0.25%ammonium hydroxide gave 1.3 g (68%) of product as a colorless solid.

MS (ES): 355 (MH⁺) for C₂₂H₃₀N₂O₂

¹H NMR (DMSO-D6) δ 1.44-1.58 (m, 1H); 1.64 (d, 1H); 1.79-2.08 (m, 2H);2.32 (t, 2H); 2.36-2.45 (m, 1H); 2.88 (d, 1H); 3.13 (d, 1H); 3.30 (s,3H); 3.40-3.49 (m, 2H); 3.56 (s, 1H); 3.59-3.87 (m, 4H); 4.34 (s, 1H);7.11-7.24 (m, 2H); 7.24-7.40 (m, 8H)

Example 847-Fluoro-2-oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-1,2-dihydroquinoline-5-carbonitrileand Example 855-Fluoro-2-oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-1,2-dihydroquinoline-7-carbonitrile

A mixture of the regioisomers1-[2-(4-aminopiperidin-1-yl)ethyl]-7-fluoro-2-oxo-1,2-dihydroquinoline-5-carbonitrile(major isomer) and1-[2-(4-aminopiperidin-1-yl)ethyl]-5-fluoro-2-oxo-1,2-dihydroquinoline-7-carbonitrile(minor isomer) (Intermediates 171 and 172, 120 mg, 0.38 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (68 mg, 0.38 mmol) and sodium triacetoxy borohydride (230mg, 1.1 mmol) were reacted as described according to Example 69.Chromatography on silica gel with 10% methanol in dichloromethanecontaining 0.5% ammonium hydroxide followed by reverse phase HPLC on a50×250 mm ODS AQ column eluting with an isocratic gradient of 15%acetonitrile in water containing 0.1% TFA to give the bis TFA salts ofExample 84 (68 mg) and Example 85 (21 mg), both as colorless solids.

Example 84

MS (ES): 477 (MH⁺) for C₂₅H₂₅FN₆O₃

¹H NMR (DMSO-D6) δ 1.09-1.27 (m, 2H); 1.67-1.83 (m, 2H); 2.00 (t, 2H);2.31-2.44 (m, 1H); 2.51-2.55 (m, 2H); 2.87 (d, 2H); 3.67 (s, 2H); 4.33(t, 2H); 4.53-4.64 (m, 2H); 6.81 (d, 1H); 7.00 (d, 1H); 7.28 (d, 1H);7.78-7.92 (m, 2H); 7.98 (d, 1H); 11.16 (s, 1H).

Example 85

MS (ES): 477 (MH⁺) for C₂₅H₂₅FN₆O₃

¹H NMR (DMSO-D6) δ 1.12-1.30 (m, 2H); 1.69-1.83 (m, 2H); 1.95-2.10 (m,2H); 2.33-2.46 (m, 1H); 2.51-2.57 (m, 2H); 2.89 (d, 2H); 3.68 (s, 2H);4.31-4.43 (m, 2H); 4.57-4.64 (m, 2H); 6.84 (d, 1H); 7.01 (d, 1H); 7.29(d, 1H); 7.70 (d, 1H); 7.99 (s, 1H); 8.06 (d, 1H); 11.17 (s, 1H).

Intermediate 171:1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-fluoro-2-oxo-1,2-dihydroquinoline-5-carbonitrile(major isomer)

and

Intermediate 172:1-[2-(4-Aminopiperidin-1-yl)ethyl]-5-fluoro-2-oxo-1,2-dihydroquinoline-7-carbonitrile

A mixture of tert-butyl{1-[2-(5-cyano-7-fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamateand tert-butyl{1-[2-(7-cyano-5-fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediates 173 and 174, 170 mg, 0.41 mmol) was reacted withtrifluoroacetic acid in dichloromethane as described for Intermediate140 to give 120 mg (92% yield) of the mixture of regioisomers as an oil.This mixture was carried on without further purification to the nextstep.

MS (ES): 315 (MH⁺) for C₁₇H₁₉FN₄O

Intermediate 173: tert-Butyl{1-[2-(5-cyano-7-fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

and

Intermediate 174: tert-Butyl{1-[2-(7-cyano-5-fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

A mixture of tert-butyl{1-[2-(5-bromo-7-fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamateand tert-butyl{1-[2-(7-bromo-5-fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediates 175 and 176, 460 mg, 0.98 mmol) was reacted withpotassium cyanide (96 mg, 1.5 mmol), tributyl tin chloride (14 μL/mL inheptane, 0.90 μL, 0.003 mmol),4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (XANTPHOS) (3.0 mg,0.005 mmol) and tris(dibenzylideneacetone)dipalladium (0) (5.0 mg, 0.005mmol) as described for Intermediate 15. Chromatography on silica gelwith acetone/hexanes (1:4) gave 170 mg of the mixture of regioisomers.This mixture was carried on directly to the next step.

MS (ES): 415 (MH⁺) for C₂₂H₂₇FN₄O₃

Intermediate 175: tert-Butyl{1-[2(5-bromo-7-fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

and

Intermediate 176: tert-Butyl{1-[2-(7-bromo-5-fluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

A mixture of 5-bromo-7-fluoroquinolin-2(1H)-one and7-bromo-5-fluoroquinolin-2(1H)-one (Intermediate 177 and 178, 3.0 g, 9.4mmol) was reacted with sodium hydride (60% in oil, 0.20 g, 5.0 mmol) and2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6, 9.4 mmol) as described for Intermediate 141.Chromatography on silica gel with a gradient of 50-75% ethyl acetate inhexanes gave 0.63 g (33%) of the regioisomeric product mixture, whichwas carried on without further purification to the next step.

MS (ES): 468, 470 (MH⁺) for C₂₁H₂₇BrFN₃O₃

Intermediate 177: 5-Bromo-7-fluoroquinolin-2(1H)-one

and

Intermediate 178: 7-Bromo-5-fluoroquinolin-2(1H)-one

The compounds were prepared from(2E)-N-(3-bromo-5-fluorophenyl)-3-phenylacrylamide (Intermediate 179,3.0 g, 9.4 mmol) and aluminium trichloride (6.2 g, 46.9 mmol) asdescribed for Intermediate 17, but the reaction mixture was heated to90° C. for 30 min, to give 1.5 g of 3:1 mixture of5-Bromo-7-fluoroquinolin-2(1H)-one and7-bromo-5-fluoroquinolin-2(1H)-one. This mixture was carried on to thenext step without further purification.

MS (ES): 242, 244 (MH⁺) for C₉H₅BrFNO

Intermediate 179: (2E)-N-(3-Bromo-5-fluorophenyl)-3-phenylacrylamide

The compound was prepared from 3-bromo-5-fluoroaniline (Intermediate180, 5.3 g, 27.9 mmol) and cinnamoylchloride (5.6 g, 33.5 mmol) in thepresence of 2,6-lutidine (5.0 mL, 41.9 mmol) as described forIntermediate 18 to give the product as a colorless solid, 7.6 g (85%yield).

MS (ES): 320, 322 (MH⁺) for C₁₅H₁₁BrFNO

¹H NMR (DMSO-D6) δ 6.77 (d, 1H); 7.18-7.30 (m, 1H); 7.40-7.52 (m, 3H);7.55-7.70 (m, 4H); 7.75 (s, 1H); 10.56 (s, 1H).

Intermediate 180: 3-Bromo-5-fluoroaniline

To a solution of N-(3-bromo-5-fluorophenyl)acetamide (Intermediate 181,8.7 g, 37.4 mmol) in ethanol (30 mL) was added concentrated hydrochloricacid (80 mL). The reaction was heated to 100° C. for 1 hr. It was cooledto room temperature and neutralized with 5N sodium hydroxide. The crudeproduct was extracted with ethyl acetate (2×100 mL), the combinedorganic layers were washed with brine, dried over magnesium sulfate,filtered, and concentrated to dryness. Chromatography on silica gel witha gradient of 5-10% ethyl acetate in hexanes gave 5.3 g (75%) of theproduct as a yellow oil.

MS (ES): 190, 192 (MH⁺) for C₆H₅BrFN

¹H NMR (DMSO-D6) δ 5.46-6.00 (m, 2H); 6.24-6.37 (m, 1H); 6.44-6.53 (m,1H); 6.54-6.61 (m, 1H).

Intermediate 181: N-(3-Bromo-5-fluorophenyl)acetamide

A mixture of acetamide (2.8 g, 47.2 mmol), palladium acetate (0.50 g,0.80 mmol), XANTPHOS (0.68 g, 1.2 mmol) and cesium carbonate (18 g, 55.2mmol) was degassed and purged with nitrogen twice. Dry dioxane (50 mL)was added followed by 1,3-dibromo-5-fluorobenzene (10 g, 39.4 mmol). Thereaction was heated to 105° C. overnight and then allowed to cool toroom temperature. Dichloromethane was added and the mixture was stirredvigorously for 1 hr. The mixture was filtered. The filtrate wasconcentrated to dryness. Chromatography on silica gel with 25% ethylacetate in hexanes gave 4.0 g (44%) of the product as a colorless solid.

MS (ES): 232, 234 (MH⁺) for C₈H₇BrFNO

1H NMR (DMSO-D6) δ 2.01-2.13 (m, 3H); 7.13-7.24 (m, 1H); 7.42-7.54 (m,1H); 7.57-7.67 (m, 1H); 10.22-10.35 (m, 1H).

Example 867-Fluoro-1-[2-(4-{[(2-oxo-1,2-dihydroquinolin-3-yl)methyl]amino}piperidin-1-yl)ethyl]quinoxalin-2(1H)-one

A mixture of1-[2-(4-aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one(Intermediate 140, 130 mg, 0.448 mmol),2-oxo-1,2-dihydroquinoline-3-carbaldehyde (65 mg, 0.448 mmol) and 3 Åmolecular sieves (100 mg) in methanol (6.0 mL) was heated at reflux for2.5 hours under nitrogen atmosphere. It was cooled to 0° C. and sodiumtriacetoxy borohydride (189.5 mg, 0.996 mmol) was added and the mixturewas allowed to warm to room temperature and stirred overnight. Themixture was filtered and purified through silica gel plug (eluting with15% methanol in methylene chloride) to give title compound (71 mg).

MS (ES): 448.52 (MH⁺) for C₂₅H₂₆FN₅O₂

¹H NMR (DMSO-D6) δ 1.13-1.32 (m, 2H); 1.79 (d, 2H); 2.02 (t, 2H);2.35-2.45 (m, 1H); 2.52-2.59 (m, 2H); 2.90 (d, 2H); 3.61 (s, 2H); 4.27(t, 2H); 7.15 (t, 1H); 7.24-7.33 (m, 2H); 7.43 (t, 1H); 7.51 (d, 1H);7.63 (d, 1H); 7.79-7.92 (m, 2H); 8.17 (s, 1H).

Example s 87-96

The following compounds were synthesized following the proceduredescribed for Example 86, except the compounds were purified by reversephase HPLC with methanol/water, containing 0.1% TFA to give the TFAsalts of the final products.

Ex Compound ¹H NMR (DMSO-D6) δ ppm ES Aldehyde 871-[2-(4-{[(2,2-Dimethyl- 1.27 (s, 6H); 1.64-1.89 (m, 4H); 4822,2-dimethyl 3,4-dihydro-2H- 2.21-2.39 (m, 2H); 2.73 (t, 2H); (MH)⁺chromane-6- chromen-6-yl)methyl] 2.95-3.18 (m, 2H); 3.80 (s, 2H);carbaldehyde amino}piperidin-1- 4.08 (s, 2H); 4.53 (s, 2H); 6.67 (d,yl)ethyl]-5,7-difluoro 1H); 6.76 (d, 1H); 7.19 (d, 1H);quinolin-2(1H)-one 7.24 (s, 1H); 7.31 (t, 1H); 7.43 (d, 1H); 8.03 (d,1H); 9.02 (s, 2H); 9.75 (s, 1H) 88 1-[2-(4-{[(1,3-Dimethyl- 1.80 (s,2H); 2.34 (s, 2H); 3.01- 482 1,3-dimethyl- 2-oxo-2,3-dibydro-1H- 3.18(m, 2H); 3.45 (s, 6H); 3.80 (MH)⁺ 2-oxo-2,3- benzimidazol-5-yl) (s, 2H);4.24 (s, 2H); 4.53 (s, 2H); dihydro-1H- methyl]amino}piperidin- 6.67 (d,1H); 7.22 (s, 2H); 7.25- benzimidazole- 1-yl)ethyl]-5,7- 7.36 (m, 2H);7.43 (d, 1H); 8.03 5- difluoroquinolin-2(1H)- (d, 1H); 9.18 (s, 2H)carbaldehyde one 89 5,7-Difluoro-1-(2-{4- 1.72 (s, 4H); 1.77-1.92 (m,2H); 452 5,6,7,8- [(5,6,7,8-tetrahydro- 2.32 (s, 2H); 2.71 (s, 4H); 3.09(s, (MH)⁺ tetrahydro- naphthalen-2-ylmethyl) 2H); 3.58 (s, 2H); 3.79 (s,2H); naphthalene-2- amino]piperidin-1-yl} 4.12 (s, 2H); 4.54 (s, 2H);6.66 (d, carbaldehyde ethyl)quinolin-2(1H)-one 1H); 7.07-7.14 (m, 1H);7.20 (s, 2H); 7.30 (t, 1H); 7.43 (d, 1H); 8.02 (d, 1H); 9.23 (s, 2H) 905,7-Difluoro-1-[2-(4- 1.84 (d, 2H); 2.33 (s, 2H); 3.09 (s, 4746-fluoro-4H- {[(6-fluoro-4H-1,3- 2H); 3.29-3.44 (m, 2H); 3.80 (s, (MH)⁺1,3- benzodioxin-8-yl)methyl] 2H); 4.16 (s, 2H); 4.54 (s, 2H);benzodioxine- amino}piperidin-1-yl) 4.91 (s, 2H); 5.32 (s, 2H); 6.66 (d,8- ethyl]quinolin-2(1H)-one 1H); 7.01-7.14 (m, 1H); 7.19- carbaldehyde7.34 (m, 2H); 7.43 (d, 1H); 8.01 (d, 1H); 9.35 (s, 2H) 915,7-Difluoro-1-(2-{4- 1.85 (d, 2H); 2.35 (s, 2H); 3.09 (s, 4371H-indole-6- [(1H-indol-6-ylmethyl) 2H); 3.31 (s, 2H); 3.80 (s, 2H);(MH)⁺ carbaldehyde amino]piperidin-1- 4.30 (s, 2H); 4.54 (s, 2H); 6.45(s, yl}ethyl)quinolin-2(1H)- 1H); 6.66 (d, 1H); 7.13 (d, 1H); one 7.29(t, 1H); 7.42 (s, 2H); 7.50- 7.68 (m, 2H); 8.01 (d, 1H); 9.22 (s, 2H);11.39 (s, 1H) 92 1-(2-{4-[(2,3-Dihydro- 1.73-1.89 (m, 2H); 1.94-2.09 438indane-5- 1H-inden-5-ylmethyl) (m, 2H); 2.22-2.41 (m, 2H); 2.86 (MH)⁺carbaldehyde amino]piperidin-1- (t, 4H); 3.28 (s, 2H); 3.43-3.54yl}ethyl)-5,7- (m, 2H); 3.78 (s, 2H); 4.16 (s, difluoroquinolin-2(1H)-2H); 4.53 (s, 2H); 6.67 (d, 1H); one 7.20-7.31 (m, 3H); 7.37 (s, 1H);7.42 (d, 1H); 8.02 (d, 1H); 9.15 (s, 2H) 93 5,7-Difluoro-1-[2-(4-1.72-1.95 (m, 2H); 2.35 (s, 2H); 453 1-methyl-1H- {[(1-methyl-1H-1,2,3-2.99-3.18 (m, 2H); 3.31 (s, 2H); (MH)⁺ 1,2,3- benzotriazol-5-yl)methyl]3.79 (s, 2H); 4.32 (s, 3H); 4.41 (s, benzotriazole- amino}piperidin-1-2H); 4.54 (s, 2H); 6.66 (d, 1H); 5- yl)ethyl]quinolin-2(1H)- 7.29 (t,1H); 7.42 (d, 1H); 7.69 (d, carbaldehyde one 1H); 7.94 (d, 1H); 8.02 (d,1H); 8.23 (s, 1H); 9.43 (s, 2H) 94 5,7-Difluoro-1-(2-{4- 1.80 (s, 2H);2.36 (s, 2H); 3.11 (s, 437 1H-indole-5- [(1H-indol-5-ylmethyl) 2H); 3.40(s, 2H); 3.80 (s, 2H); (MH)⁺ carbaldehyde amino]piperidin-1- 4.26 (s,2H); 4.52 (s, 2H); 6.47 (s, yl}ethyl)quinolin-2(1H)- 1H); 6.67 (d, 1H);7.21 (d, 1H); one 7.31 (t, 1H); 7.37-7.52 (m, 3H); 7.70 (s, 1H); 8.03(d, 1H); 9.04 (s, 1H); 11.28 (s, 1H) 95 5,7-Difluoro-1-[2-(4- 1H NMR(DMSO-D6) δ ppm 1.73 469 4-methyl-3,4- {[(4-methyl-3,4-dihydro- (s, 2H);2.30 (s, 2H); 2.83 (s, 3H); (MH)⁺ dihydro-2H- 2H-1,4-benzoxazin-7-yl)2.97-3.15 (m, 2H); 3.24 (s, 2H); 1,4- methyl]amino}piperidin- 3.30-3.38(m, 2H); 3.79 (s, 2H); benzoxazine- 1-yl)ethyl]quinolin- 4.03 (s, 2H);4.22 (s, 2H); 4.53 (s, 7- 2(1H)-one 2H); 6.63-6.75 (m, 2H); 6.85 (s,carbaldehyde 1H); 6.90 (d, 1H); 7.31 (t, 1H); 7.43 (d, 1H); 8.04 (d,1H); 8.90 (s, 1H) 96 1-(2-{4-[(2,1,3- 1.13-1.29 (m, 2H); 1.78 (d, 2H);423 2,1,3- Benzoxadiazol-5- 1.95-2.07 (m, 2H); 2.31-2.43 (MH)⁺benzoxadiazole- ylmethyl)amino] (m, 1H); 2.51-2.58 (m, 2H); 2.89 5-piperidin-1-yl}ethyl)-7- (d, 2H); 3.82 (s, 2H); 4.27 (t, 2H);carbaldehyde fluoroquinoxalin-2(1H)- 7.23 (td, 1H); 7.51 (dd, 1H); 7.58one (d, 1H); 7.80-7.89 (m, 2H); 7.96 (d, 1H); 8.18 (s, 1H)

Example 97N-{1-[2-(7-Fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}-2,3-dihydro-1,4-benzodioxine-6-sulfonamide

To a solution of1-[2-(4-aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one(Intermediate 140, 130 mg, 0.448 mmol) in methylene chloride (10 mL) wasadded diisopropylethylamine (0.156 mL, 0.996 mmol) and2,3-dihydro-1,4-benzodioxine-6-sulfonyl chloride (116 mg, 0.493 mmol)and the reaction was stirred for 2.5 hours at room temperature. It waswashed with saturated sodium bicarbonate solution and brine, dried oversodium sulfate, and concentrated. The residue was dissolved in HCl indioxane (4M, 8.0 mL), concentrated, suspended in ethyl acetate andfiltered to give the HCl salt of title compound (15.9 mg).

MS (ES): 489 (MH⁺) for C₂₃H₂₅FN₄O₅S

¹H NMR (DMSO-D6) δ 1.62-1.83 (m, 3H); 2.92-3.11 (m, 2H); 3.16-3.28 (m,3); 3.41-3.50 (m, 3H); 3.59 (d, 2H); 4.47-4.59 (m, 2H); 7.05 (d, 1H);7.23-7.34 (m, 2H); 7.78 (dd, 1H); 7.83-7.96 (m, 2H); 8.15-8.23 (m, 1H);10.61 (s, 1H).

Example 98N-{1-[2-(7-Fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonamide

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one(Intermediate 140, 130 mg, 0.448 mmol) was reacted as described forExample 97 with 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-sulfonyl chloride(122 mg, 0.493 mmol) to give the HCl salt of title compound (89 mg).

MS (ES): 502 (MH⁺) for C₂₃H₂₄FN₅O₅S

¹H NMR (DMSO-D6) δ 1.55-1.93 (m, 3H); 2.94-3.09 (m, 2H); 3.17-3.30 (m,2H); 3.50 (d, 1H); 3.61 (d, 2H); 4.53 (d, 2H); 4.69 (s, 2H); 7.12 (d,1H); 7.28 (t, 1H); 7.32-7.42 (m, 2H); 7.73 (d, 1H); 7.83-7.95 (m, 1H);8.02 (d, 1H); 8.20 (s, 1H); 10.14 (s, 1H); 11.04 (s, 1H).

Example 995-Fluoro-N-{1-[2-(7-fluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}-1H-indole-2-carboxamide

A mixture of1-[2-(4-aminopiperidin-1-yl)ethyl]-7-fluoroquinoxalin-2(1H)-one(Intermediate 140, 130 mg, 0.448 mmol), 5-fluoro-1H-indole-2-carboxylicacid (96.3 mg, 0.538 mmol),N-(3-Dimethylaminopropyl)-N-ethylcarbodiimide (EDC)(124 mg, 0.645 mmol)and 1-Hydroxybenzotriazole hydrate (HOBT) (87 mg, 0.645 mmol) indichloromethane/DMF (4:1, 10 mL) was stirred for 2.5 hours at roomtemperature. The solvent was removed under reduced pressure and theresidue was suspended in methanol, stirred for 45 minutes and thenfiltered to give title compound (161 mg).

MS (ES): 452 (MH⁺) for C₂₄H₂₃F₂N₅O₂

¹H NMR (DMSO-D6) δ 1.78-2.15 (m, 4H); 3.10-3.29 (m, 2H); 3.57 (s, 1H);3.75 (d, 2H); 4.07 (s, 1H); 4.61 (s, 2H); 6.95-7.10 (m, 1H); 7.19 (s,1H); 7.23-7.34 (m, 1H); 7.39 (d, 2H); 7.75-7.88 (m, 1H); 7.88-7.98 (m,1H); 8.23 (s, 1H); 8.67 (d, 1H); 10.44 (s, 1H); 11.74 (s, 1H).

Example 100N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}-6-morpholin-4-ylnicotinamide

1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one(Intermediate 23, 100 mg, 0.326 mmol) was reacted as described forExample 99 with 6-morpholin-4-ylnicotinic acid (81 mg, 0.391 mmol), EDC(94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mmol) to give title compound(43.6 mg).

MS (ES): 498 (MH⁺) for C₂₆H₂₉F₂N₅O₃

¹H NMR (DMSO-D6) δ 1.81-2.12 (m, 5H); 3.09-3.24 (m, 2H); 3.46-3.60 (m,4H); 3.62-3.78 (m, 6H); 3.97-4.18 (m, 1H); 4.63 (s, 2H); 6.67 (d, 1H);6.85 (d, 1H); 7.30 (t, 1H); 7.74 (d, 1H); 7.93-8.07 (m, 2H); 8.37 (d,1H); 8.63 (s, 1H); 10.66 (s, 1H).

Example 101N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(217)-yl)ethyl]piperidin-4-yl}-2,3-dihydro-1,4-benzodioxine-2-carboxamide

1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one(Intermediate 23, 100 mg, 0.326 mmol) was reacted as described forExample 99 with 2,3-dihydro-1,4-benzodioxine-2-carboxylic acid (71 mg,0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mmol) togive title compound (73.9 mg).

MS (ES): 470 (MH⁺) for C₂₅H₂₅F₂N₃O₄

¹H NMR (DMSO-D6) δ 1.71-2.05 (m, 4H); 3.06-3.21 (m, 2H); 3.22-3.29 (m,2H); 3.67 (s, 1H); 3.80-4.03 (m, 1H); 4.17 (dd, 1H); 4.31-4.45 (m, 1H);4.51-4.67 (m, 2H); 4.70-4.79 (m, 1H); 6.58-6.73 (m, 1H); 6.85 (d, 2H);6.92-7.02 (m, 1H); 7.30 (t, 1H); 7.65 (d, 1H); 8.03 (d, 1H); 8.41 (d,1H); 10.19 (s, 1H).

Example 102N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}-1-methyl-1H-1,2,3-benzotriazole-5-carboxamide

1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one(Intermediate 23, 100 mg, 0.326 mmol) was reacted as described forExample 99 with 1-methyl-1H-1,2,3-benzotriazole-5-carboxylic acid (70mg, 0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mol) togive title compound (67.6 mg).

MS (ES): 467 (MH⁺) for C₂₄H₂₄F₂N₆O₂

¹H NMR (DMSO-D6) δ 1.86-2.03 (m, 2H); 2.07 (s, 2H); 3.12-3.25 (m, 2H);3.42-3.61 (m, 1H); 3.73 (d, 2H); 4.09 (s, 1H); 4.33 (s, 3H); 4.64 (t,2H); 6.68 (d, 1H); 7.30 (t, 1H); 7.73 (d, 1H); 7.92 (d, 1H); 8.05 (t,2H); 8.61 (s, 1H); 8.76 (d, 1H); 10.60 (s, 1H).

Example 103N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}-3-(2-methyl-1,3-thiazol-4-yl)benzamide

1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one(Intermediate 23, 100 mg, 0.326 mmol) was reacted as described forExample 99 with 3-(2-methyl-1,3-thiazol-4-yl)benzoic acid (86 mg, 0.391mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mmol). Solventremoved and the obtained solids were stirred in HCl/dioxane (8.0 mL, 4M)and then filtered to give the HCl salt of title compound (39 mg).

MS (ES): 509 (MH⁺) for C₂₇H₂₆F₂N₄O₂S

¹H NMR (DMSO-D6) δ 1.91-2.17 (m, 4H); 2.73 (s, 3H); 3.10-3.39 (m, 3H);3.50 (s, 1H); 3.71 (d, 2H); 4.64 (s, 2H); 6.68 (d, 1H); 7.30 (t, 1H);7.51 (t, 1H); 7.72-7.89 (m, 2H); 7.98-8.13 (m, 3H); 8.42 (s, 1H); 8.73(d, 1H); 10.85 (s, 1H).

Example 104N-{1-[2-(5,7-Difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidin-4-yl}-4-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide

1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one(Intermediate 23, 100 mg, 0.326 mmol) was reacted as described forExample 99 with 4-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (80 mg,0.391 mmol), EDC (94 mg, 0.489 mmol) and HOBT (66 mg, 0.489 mmol).Solvent removed and the obtained solids were suspended in ethyl acetateand then filtered to give title compound (71.9 mg).

MS (ES): 494 (MH⁺) for C₂₆H₂₅F₂N₅O₃

¹H NMR (DMSO-D6) δ 1.77-1.97 (m, 2H); 1.98-2.15 (m, 2H); 2.68 (s, 3H);3.10-3.27 (m, 2H); 3.75 (d, 2H); 4.05 (s, 1H); 4.60 (t, 2H); 6.69 (d,1H); 7.32 (t, 1H); 7.46-7.68 (m, 1H); 7.96-8.15 (m, 5H); 8.72 (d, 1H);9.86 (s, 1H).

Example 1053-Oxo-4-[2-((2R,5S)-5-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

To a solution of tert-butyl(2R,5S)-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-5-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidine-1-carboxylate(Intermediate 182, 0.138 g) in dioxane (2 mL) was added 4M HCl/dioxane(1 mL). After 1 hour at room temperature, the reaction was concentratedand evaporated twice from methanol. The solid was suspended in methanoland filtered to yield 73 mg of the name compound as a bis HCl salt.

MS (ESI) 463 (MH⁺) for C₂₄H₂₆N₆O₄

¹H NMR (DMSO-D6) δ 1.58-1.63 (m, 1H); 1.65-1.74 (m, 1H); 1.75-1.86 (m,1H); 1.92-2.03 (m, 1H); 2.13-2.23 (m, 1H); 2.29-2.38 (m, 1H); 3.02-3.14(m, 1H); 3.14-3.24 (m, 3H); 3.59-3.70 (m, 1H); 3.70-3.78 (m, 1H);4.01-4.13 (m, 2H); 4.18-4.28 (m, 2H); 4.70 (s, 2H); 4.82 (s, 2H); 7.19(d, 1H); 7.26 (d, 1H); 7.46 (d, 1H); 7.54 (dd, 1H); 7.77 (d, 1H); 9.51(s, 1H); 9.70 (s, 1H); 9.82 (s, 1H); 11.36 (s, 1H).

Intermediate 182: tert-Butyl(2R,5S)-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-5-{[(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidine-1-carboxylate

A mixture of tert-butyl(2R,5S)-5-amino-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate(Intermediate 183, 0.14 g),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (75 mg) and 3 Å molecular sieves powder (70 mg) in methanol(8 mL) was heated at 80° C. for 1 hour. The solution was cooled to 0° C.and NaCNBH₃ (33 mg) was added. After stirring at room temperatureovernight, the reaction was filtered and concentrated. The residue waspurified chromatography on silica gel with a gradient of 0-5% methanolin methylene chloride to give 0.14 g.

MS (ESI) 563 (MH⁺) for C₂₉H₃₄N₆O₆

¹H NMR (CDCl₃) δ 1.37-1.43 (m, 1H); 1.44-1.51 (s, 9H); 1.70-1.81 (m,2H); 2.11 (m, 1H); 2.89-3.00 (m, 1H); 3.01-3.12 (m, 1H); 3.94-4.05 (m,1H); 4.20-4.32 (m, 1H); 4.33-4.44 (m, 1H); 4.64 (s, 2H); 4.67 (s, 2H);6.99 (d, 1H); 7.04 (d, 1H); 7.17-7.24 (m, 2H); 7.32 (dd, 1H).

Intermediate 183: tert-Butyl(2R,5S)-5-amino-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate

tert-Butyl(2R,5S)-5-azido-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate(Intermediate 184, 0.31 g) was hydrogenated in methanol (10 mL) over 10%Pd/C (90 mg) at normal pressure and room temperature overnight. Thereaction was degassed, filtered and purified by chromatography on silicagel with a gradient of 0-10% methanol in methylene chloride to give 0.29g.

MS (ESI) 401 (MH⁺) for C₂₁H₂₈N₄O₄

Intermediate 184: tert-Butyl(2R,5S)-5-azido-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate

To a solution of tert-butyl(2R,5R)-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-5-hydroxypiperidine-1-carboxylate(Intermediate 185, crude, 0.8 g) in THF (20 mL) were successively addedtriphenylphosphine (1.30 g), diisopropylazodicarboxylate (1 mL) anddiphenyl phosphoryl azide (0.90 g). After 4 hours, the reaction wasdiluted with ethyl acetate, washed with saturated solution of sodiumhydrogen carbonate (NaHCO₃) and brine, dried over sodium sulfate andconcentrated. Chromatography on silica gel with a gradient of 0-5%methanol in methylene chloride gave 0.31 g of product.

MS (ER) 427 (MH⁺) for C₂₁H₂₆N₆O₄

Intermediate 185: tert-Butyl(2R,5R)-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]-5-hydroxypiperidine-1-carboxylate

To a solution of tert-butyl(2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate(Intermediate 186, 1.01 g) in THF (10 mL) was added tetrabutylammoniumfluoride (TBAF) (4 mL). After 5 hours, the reaction was diluted withethyl acetate, washed with NaHCO₃ and brine, dried over sodium sulfateand concentrated. The crude reaction mixture was used without furtherpurification in the next step.

MS (EST) 402 (MH⁺) for C₂₁H₂₇N₃O₅

Intermediate 186: tert-Butyl(2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate

To a solution of tert-butyl(2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-hydroxyethyl)piperidine-1-carboxylate(Intermediate 187, 1.27 g) in methylene chloride (15 mL) at 0° C. wereadded diisopropylethylamine (1.2 mL) and methanesulfonyl chloride (0.50mL). At the same time in a separate flask, to a solution of3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 60)(0.66 g) in DMF (8 mL) at 0° C. was added 60% suspension in oil of NaH(0.25 g). After 30 minutes, the mesylate solution was diluted withmethylene chloride, washed with NaHCO₃ and brine, dried over sodiumsulfate and concentrated. This residue was dissolved in DMF (5 mL) andadded to the sodium salt of Intermediate 60. The reaction was stirredover the weekend, diluted with ethyl acetate, washed with NaHCO₃ andbrine, dried over sodium sulfate and concentrated to give the product.

MS (ESI) 516 (MH⁺) for C₂₇H₄₁N₃O₅Si

Intermediate 187:tert-Butyl(2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-hydroxyethyl)piperidine-1-carboxylate

To a solution of tert-butyl(2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-vinylpiperidine-1-carboxylate(Intermediate 188, 1.39 g) in THF (20 mL) at 0° C. was added 9-BBN (0.5M, 15 mL). After 45 minutes, the reaction was diluted with water (3 mL),3 N NaOH (12 mL) and 30% H₂O₂ (12 mL). After 15 minutes, the reactionwas allowed to warm to room temperature. After 30 minutes, the reactionwas diluted with ethyl acetate, washed with 1 N HCl, NaHCO₃ and brine,dried (Na₂SO₄), filtered and concentrated. Chromatography on silica gelwith a gradient of 0-5% methanol in methylene chloride gave 1.27 g ofproduct.

MS (ESI) 360 (MH⁺) for C₁₈H₃₇NO₄Si

Intermediate 188: tert-Butyl(2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-vinylpiperidine-1-carboxylate

To a suspension of zinc dust (12.2 g) in THF (200 mL) and diiodomethane(5 mL) at 0° C. was added trimethylaluminium (2M in hexanes, 6 mL).After the addition the reaction was carefully warmed to room temperature(exothermic reaction!). The reaction was then cooled with an ice bathand a solution of tert-butyl(2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-formylpiperidine-1-carboxylate(Intermediate 189, 6.84 g) in THF (40 mL) was added. After 6 hours itwas warmed to room temperature, the reaction was diluted with ethylacetate and slowly quenched with a saturated aqueous solution of NaHCO₃.The organic phase was collected and washed with NaHCO₃ and brine, dried(Na₂SO₄), filtered and concentrated. Chromatography on silica gel with agradient of 0-100% methylene chloride in hexanes gave 3.96 g of product.

MS (ESI) 341 (MH⁺) for C₁₈H₃₅NO₃Si

¹H NMR (CDCl₃) δ 0.06 (s, 6H); 0.87 (s, 9H); 1.42-1.44 (m, 1H); 1.44 (s,9H); 1.63-1.81 (m, 2H); 2.44-2.73 (m, 1H); 3.43-3.63 (m, 1H); 3.77-4.16(m, 1H); 4.50-4.92 (m, 1H); 4.97-5.13 (m, 1H); 5.13-5.26 (m, 1H);5.58-5.84 (m, 1H).

Intermediate 189: tert-Butyl(2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-formylpiperidine-1-carboxylate

To a solution of oxalyl chloride (2.4 mL) in methylene chloride (75 mL)at −78° C. was slowly added dimethylsulfoxide (3 mL) in methylenechloride (25 mL). After 10 minutes, a solution of tert-butyl(2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)piperidine-1-carboxylate(Intermediate 190, 7.60 g) in methylene chloride (40 mL) was slowlyadded. After 30 minutes at −78° C., diisopropylethylamine (10 mL) wasadded and the reaction warmed to room temperature. The reaction wasdiluted with ethyl acetate, washed with 0.5 M HCl, NaHCO₃ and brinesolutions, dried (Na₂SO₄), filtered and concentrated. Chromatography onsilica gel with a gradient of 0-30% ethyl acetate in hexanes gave 6.84 gof product.

MS (ESI) 344 (MH⁺) for C₁₇H₃₃NO₄Si

Intermediate 190: tert-Butyl(2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)piperidine-1-carboxylate

To a solution of 1-tert-butyl 2-ethyl(2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}piperidine-1,2-dicarboxylate(Intermediate 191, 9.99 g) in THF (100 mL) was added lithium aluminiumhydride (1M in THF, 30 mL). After 2 hours, the reaction was quenchedwith ethyl acetate, washed with 1 N HCl, NaHCO₃ and brine solutions,dried (Na₂SO₄), filtered and concentrated yielding 7.9 g of product.

MS (ESI) 346 (MH⁺) for C₁₇H₃₅NO₄Si

Intermediate 191: 1-tert-Butyl 2-ethyl(2R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}piperidine-1,2-dicarboxylate

To a solution of 1-tert-butyl 2-ethyl(2R)-5-oxopiperidine-1,2-dicarboxylate (8.8 g) (Bioorganic & MedicinalChemistry Letters (2002), 12(10), 1387-1390) in methanol (200 mL) at 0°C. was added sodium borohydride (1.80 g). After 2 hours, the reactionwas concentrated to dryness. The residue was dissolved in ethyl acetateand washed with 1 N HCl, NaHCO₃ and brine solutions, dried (Na₂SO₄),filtered and concentrated. The crude alcohol was dissolved in DMF (200mL) and tread with imidazole (7.5 g) and t-BDMSCl (11.5 g). Afterstirring overnight at room temperature, the reaction was diluted withethyl acetate and washed with 1 N HCl, NaHCO₃ and brine solutions, dried(Na₂SO₄), filtered and concentrated. Chromatography on silica gel with agradient of 0-25% ethyl acetate in hexanes gave 9.99 g of product.

MS (ESI) 388 (MH⁺) for C₁₉H₃₇NO₅Si

1H NMR (CDCl₃) δ (rotamers) 0.06 (m, 6H); 0.86 & 0.87 (s, 9H); 1.22-1.30(m, 3H); 1.42 & 1.46 (s, 9H); 1.61-1.73 (m, 1H); 1.77-1.91 (m, 1H);2.18-2.31 (m, 1H); 2.58 & 2.69 (dd, 1H); 3.42-3.62 (m, 1H); 3.97 & 4.13(dd, 1H); 4.14-4.25 (m, 2H); 4.60 & 4.81 (d, 1H).

Example 1063-Oxo-4-[2-((2S,5R)-5-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-2-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

The title compound was prepared following the procedure described forExample 105, except, starting from 1-tert-butyl 2-methyl(2S)-5-oxopiperidine-1,2-dicarboxylate (Bioorganic & Medicinal ChemistryLetters (2002), 12(10), 1387-1390).

MS (ESI) 463 (MH⁺) for C₂₄H₂₆N₆O₄

¹H NMR (DMSO-D6) δ 1.58-1.63 (m, 1H); 1.65-1.74 (m, 1H); 1.75-1.86 (m,1H); 1.92-2.03 (n, 1H); 2.13-2.23 (m, 1H); 2.29-2.38 (n, 1H); 3.02-3.14(m, 1H); 3.14-3.24 (m, 3H); 3.59-3.70 (m, 1H); 3.70-3.78 (m, 1H);4.01-4.13 (m, 2H); 4.18-4.28 (n, 2H); 4.70 (s, 2H); 4.82 (s, 2H); 7.19(d, 1H); 7.26 (d, 1H); 7.46 (d, 1H); 7.54 (dd, 1H); 7.77 (d, 1H); 9.51(s, 1H); 9.70 (s, 1H); 9.82 (s, 1H); 11.36 (s, 1H).

Example 1076-[({1-[2-(5,7-Difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

To a solution of1-[2-(4-aminopiperidin-1-yl)ethyl]-5,7-difluoroquinoxalin-2(1H)-one(Intermediate 192, 0.158 g) in methanol (10 mL) were added 3 Å molecularsieve power (0.15 g) and3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (92 mg). After 2 hours at reflux, the reaction was cooledto 0° C. and NaBH(OAc)₃ (0.19 g) was added. The reaction was allowed towarm to room temperature and was stirred overnight. It was diluted withethyl acetate, filtered, washed with saturated solutions of Na₂CO₃ andbrine, dried over sodium sulfate and concentrated. Chromatography onsilica gel with 0-20% methanol in dichloromethane. Fractions containingproduct were collected, concentrated, dissolved in a minimum of CH₂Cl₂,precipitated with diethyl ether, and filtered to yield 104 mg ofproduct.

MS (ESI) 471 (MH⁺) for C₂₃H₂₄F₂N₆O₃

¹H NMR (CDCl₃) δ 1.15-1.35 (m, 2H); 1.73-1.88 (m, 2H); 1.93-2.09 (m,2H); 2.51-2.58 (m, 2H); 2.83-2.95 (m, 2H); 3.16 (d, 1H); 3.71-3.84 (m,1H); 4.21-4.34 (m, 2H); 4.61 (s, 2H); 7.02 (d, 1H); 7.26-7.48 (m, 1H);8.19 (s, 1H).

Intermediate 192:1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinoxalin-2(1H)-one

To a solution of tert-butyl{1-[2-(5,7-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 193, 0.21 g) in dioxane (3 mL) and water (1 mL) was added4 M HCl in dioxane (1 mL). After 30 minutes, additional 4 M HCl/dioxane(3 mL) was added. After 1 hour, the reaction was diluted with chloroformand poured into a saturated solution of Na₂CO₃. The organic solution wascollected, dried (Na₂SO₄), filtered and concentrated yielding 0.158 g ofcrude titled compound.

MS (ESI) 309 (MH⁺) for C₁₅H₁F₂N₄O

Intermediates 193: tert-Butyl{1-[2-(5,7-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamateand Intermediate 194: tert-Butyl{1-[2-(6,8-difluoro-2-oxoquinoxalin-1(2H-yl)ethyl]piperidin-4-yl}carbamate

A mixture of 5,7-difluoroquinoxalin-2(1H)-one and6,8-difluoroquinoxalin-2(1H)-one (Intermediate 195) (1.05 g, 5.77 mmol)was deprotonated with sodium hydride (0.31 g, 60% in oil, 7.75 mmol) andalkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethylmethanesulfonate (Intermediate 6) (5.8 mmol) as described forIntermediate 2. The residue obtained after aqueous workup was tituratedin diethyl ether and filtered yielding 0.73 g of tert-butyl{1-[2-(5,7-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 193). The filtrate was concentrated and the residue waspurified by chromatography on silica gel with 0-20% acetone indichloromethane to yield 111 mg of tert-butyl{1-[2-(6,8-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 194).

Intermediate 193

MS (ESI) 409 (MH⁺) for C₂₀H₂₆F₂N₄O₃

¹H NMR (CDCl₃) δ 1.33-1.42 (m, 2H); 1.44 (s, 9H); 1.89-1.97 (m, 2H);2.24 (td, 2H); 2.65 (t, 2H); 2.84-2.89 (m, 2H); 3.41-3.52 (m, 1H); 4.27(t, 2H); 4.41 (s, 1H); 6.87 (td, 1H); 6.93 (dt, 1H); 8.23 (s, 1H).

Intermediate 194

MS (ESI) 409 (MH⁺) for C₂₀H₂₆F₂N₄O₃

¹H NMR (CDCl₃) δ 1.31-1.42 (m, 2H); 1.44 (s, 9H); 1.86-1.96 (m, 2H);2.23 (td, 2H); 2.67 (t, 2H); 2.84-2.91 (m, 2H); 3.39-3.51 (m, 1H);4.34-4.45 (m, 1H); 4.46-4.53 (m, 2H); 7.13 (ddd, 1H); 7.36-7.44 (m, 1H);8.30 (s, 1H).

Intermediate 195: 5,7-Difluoroquinoxalin-2(1H)-one and6,8-difluoroquinoxalin-2(1H)-one

To a solution of 1,2-diamino-3,5-difluorobenzene (5.11 g) in methanol(100 mL) was added ethylglyoxalate (16 mL). After 6 hours at roomtemperature, the precipitate was collected by filtration and washed withmethanol yielding 2.1 g products, 1:1 mixture of5,7-difluoroquinoxalin-2(1H)-one and 6,8-difluoroquinoxalin-2(1H)-one.

MS (ESI) 182 (MH⁺) for C₈H₄F₂N₂O

Example 1086-[({1-[2-(6,8-Difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-6,8-difluoroquinoxalin-2(1H)-one(Intermediate 196, 52 mg) was reacted with3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) and sodium acetoxyborohydride as described for Example 107yielding 29 mg of the title compound.

MS (ESI) 471 (MH⁺) for C₂₃H₂₄F₂N₆O₃

¹H NMR (DMSO-D6) δ 1.16-1.28 (m, 2H); 1.71-1.82 (m, 2H); 2.04 (t, 2H);2.35-2.47 (m, 2H); 2.54-2.61 (m, 2H); 2.81-2.90 (m, 2H); 3.70 (s, 2H);4.32-4.42 (m, 2H); 4.61 (s, 2H); 7.02 (d, 1H); 7.30 (d, 1H); 7.61 (d,1H); 7.72 (ddd, 1H); 8.33 (s, 1H); 11.17 (s, 1H).

Intermediate 196:1-[2-(4-Aminopiperidin-1-yl)ethyl]-6,8-difluoroquinoxalin-2(1H)-one

tert-Butyl{1-[2-(6,8-difluoro-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

(Intermediate 194) was deprotected with HCl in dioxane as described forIntermediate 192.

MS (ESI) 309 (MH⁺) for C₁₅H₁₈F₂N₄O

Example 1092-Oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-1,2-dihydroquinoxaline-6-carbonitrile

1-[2-(4-Aminopiperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoxaline-6-carbonitrile(Intermediate 197, 0.125 g) was reacted with3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (0.17 g) and NaBH(OAc)₃ (0.27 g) as described for Example107. The residue was purified by reverse phase HPLC with acetonitrile inwater containing 0.1% TFA. Fractions containing product wereconcentrated to remove acetonitrile, neutralized with Na₂CO₃ solid,extracted with ethyl acetate, dried (Na₂SO₄), filtered and concentrated.The residue was suspended in diethyl ether and filtered to yield 127 mgof a colorless solid.

MS (ESI) 460 (MH⁺) for C₂₄H₂₅N₇O₃

¹H NMR (DMSO-D6) δ 1.14-1.25 (m, 2H); 1.70-1.80 (m, 2H); 1.96-2.07 (m,2H); 2.33-2.43 (m, 1H); 2.51-2.57 (m, 2H); 2.87 (d, 2H); 3.67 (s, 2H);4.33 (t, 2H); 4.61 (s, 2H); 7.01 (d, 1H); 7.30 (d, 1H); 7.79 (d, 1H);8.05 (dd, 1H); 8.36 (d, 2H); 11.16 (s, 1H).

Intermediate 197:1-[2-(4-Aminopiperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoxaline-6-carbonitrile

To a solution of tert-butyl{1-[2-(6-cyano-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 198, 0.38 g) in methylene chloride (4 mL) was added at 0°C. TFA (2 mL). After 1 hour, the reaction was diluted with chloroform,washed with saturated solution of Na₂CO₃, dried (Na₂SO₄), filtered andconcentrated yielding 0.25 g of crude product.

MS (ESI) 298 (MH⁺) for C₁₆H₁₉N₅O

Intermediate 198: tert-Butyl{1-[2-(6-cyano-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamateand Intermediate 199: tert-Butyl{1-[2-(7-cyano-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

A mixture of 2-oxo-1,2-dihydroquinoxaline-6-carbonitrile and3-oxo-3,4-dihydroquinoxaline-6-carbonitrile (Intermediate 200, 0.83 g,4.8 mmol) was deprotonated with sodium hydride (0.30 g, 60% in oil) andalkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethylmethanesulfonate (Intermediate 6) (4.8 mmol) as described forIntermediate 2. Chromatography on silica gel with 0-25% acetone indichloromethane gave 38 mg of tert-butyl{1-[2-(7-cyano-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 199) and 0.39 g of tert-butyl{1-[2-(6-cyano-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 198).

MS (ESI) 398 (MH⁺) for C₂₁H₂₇N₅O₃

Intermediate 198

¹H NMR (CDCl₃) δ 1.31-1.41 (m, 2H); 1.44 (s, 9H); 1.88-1.98 (m, 2H);2.19-2.29 (m, 2H); 2.67 (t, 2H); 2.83-2.93 (m, 2H); 3.41-3.52 (m, 1H);4.35 (t, 2H); 4.43 (m, 1H); 7.48 (d, 1H); 7.80 (dd, 1H); 8.20 (d, 1H);8.35 (s, 1H).

Intermediate 199

¹H NMR (CDCl₃) δ 1.32-1.42 (m, 2H); 1.44 (s, 9H); 1.89-1.97 (m, 2H);2.19-2.30 (m, 2H); 2.68 (t, 2H); 2.83-2.93 (m, 2H); 3.42-3.53 (m, 1H);4.33 (t, 2H); 4.42 (s, 1H); 7.59 (dd, 1H); 7.79 (s, 1H); 7.97 (d, 1H);8.37 (s, 1H).

Intermediate 200: 2-Oxo-1,2-dihydroquinoxaline-6-carbonitrile and3-oxo-3,4-dihydroquinoxaline-6-carbonitrile

To a solution of 3,4-diaminobenzonitrile (0.99 g) in methanol (20 mL)was added ethylglyoxalate (3.5 mL). After stirring overnight at roomtemperature, the precipitate was collected and washed with methanol. Thefiltrate was concentrated to give a second crop of product yielding 0.83g from both batches, 1:1 mixture of2-oxo-1,2-dihydroquinoxaline-6-carbonitrile and3-oxo-3,4-dihydroquinoxaline-6-carbonitrile as a brown solid.

MS (ESI) 172 (MH⁺) for C₉H₅N₃O

Example 1103-Oxo-4-[2-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-3,4-dihydroquinoxaline-6-carbonitrile

1-[2-(4-Aminopiperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoxaline-7-carbonitrile(Intermediate 201, 0.11 g) was reacted with3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) and sodium acetoxyborohydride as described for Example 107yielding 17 mg of a colorless solid.

MS (ESI) 460 (MH⁺) for C₂₄H₂₅N₇O₃

¹H NMR (DMSO-D6) δ 1.22-1.33 (m, 2H); 1.80-1.91 (m, 2H); 1.98-2.08 (m,2H); 2.55-2.67 (m, 3H); 2.90-3.01 (m, 2H); 3.79-3.90 (m, 1H); 4.35 (t,2H); 4.64 (s, 2H); 7.05 (d, 1H); 7.34 (d, 1H); 7.79 (d, 1H); 7.99 (d,1H); 8.21 (s, 1H); 8.38 (s, 1H); 11.23 (s, 1H).

Intermediate 201:1-[2-(4-Aminopiperidin-1-yl)ethyl]-2-oxo-1,2-dihydroquinoxaline-7-carbonitrile

tert-Butyl{1-[2-(7-cyano-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}carbamate

(Intermediate 199) was deprotected with TFA as described forIntermediate 197 to give the crude free base of the product.

MS (ESI) 298 (MH⁺) for C₁₆H₁₉N₅O

Example 1116-[({1-[2-(6-Methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one(Intermediate 202, 0.125 g) was reacted with3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (50 mg) and sodium acetoxyborohydride (110 mg) as describedfor Example 107. Chromatography on silica gel with 0-20% methanol indichloromethane and trituration of the product from ether gave 37.6 mgof the title compound as acetic acid salt.

MS (ESI) 466 (MH⁺) for C₂₃H₂₇N₇O₄

¹H NMR(DMSO-D6) δ 1.18 (q, 2H); 1.74 (d, 2H); 2.03 (t, 2H); 2.32-2.41(m, 1H); 2.61 (t, 2H); 2.90 (d, 2H); 3.66 (s, 2H); 3.98 (s, 3H); 4.41(t, 2H); 4.59 (s, 2H); 6.83 (d, 1H); 6.99 (d, 1H); 7.27 (d, 1H); 8.10(s, 1H); 8.12 (d, 1H); 11.15 (s, 1H).

Intermediate 202:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one

tert-Butyl{1-[2-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 203, 0.213 g) was deprotected with TFA as described forIntermediate 197 to give the crude free base of the product, 0.15 g.

MS (ESI) 304 (MH⁺) for C₁₅H₂₁N₅O₂

Intermediate 203: tert-Butyl{1-[2-(6-methoxy-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl)ethyl]piperidin-4-yl}carbamate

6-Methoxypyrido[2,3-b]pyrazin-3(4H)-one (Intermediate 204, 0.085 g, 0.48mmol) was deprotonated with sodium hydride (0.030 g, 60% in oil, 0.7.5mmol) and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (1.05 mmol) as described for Intermediate 2.Chromatography on silica gel with 0-25% acetone in dichloromethane gave0.13 g of the title compound.

MS (ESI) 404 (MH⁺) for C₂₀H₂₉N₅O₄

¹H NMR (CDCl₃) δ 1.31-1.40 (m, 2H); 1.40-1.46 (m, 9H); 1.87-1.95 (m,2H); 2.15-2.27 (m, 2H); 2.69-2.75 (m, 2H); 2.93-3.02 (m, 2H); 3.40-3.51(m, 1H); 4.02 (s, 3H); 4.35-4.46 (m, 1H); 4.51-4.60 (m, 2H); 6.73 (d,1H); 8.02 (d, 1H); 8.15 (s, 1H).

Intermediate 204: 6-Methoxypyrido[2,3-b]pyrazin-3(4H)-one

To a solution of 3,4-diamino-6-methoxypyridine (1.11 g) in methanol (20mL) was added ethylglyoxalate (3.5 mL). After stirring overnight at roomtemperature, it was filtered and washed with methanol (the precipitatecontained the undesired regioisomer,6-methoxypyrido[2,3-b]pyrazin-2(1H)-one). The filtrate was concentratedand suspended in diethyl ether to give 0.18 g product.

MS (ESI) 178 (MH⁺) for C₈H₇N₃O₂

¹H NMR (DMSO-D6) δ 6.77 (d, 1H); 8.01 (s, 1H); 8.07 (d, 1H); 12.83 (s,1H).

Example 1124-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one(Intermediate 202, 75 mg) was reacted with2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(48 mg) and sodium acetoxyborohydride (0.11) as described for Example107. Chromatography on silica gel with 0-2% methanol in dichloromethaneto give 72 mg of the product.

MS (ESI) 453 (MH⁺) for C₂₃H₂₈N₆O₄

¹H NMR (DMSO-D6) δ 1.18 (q, 2H); 1.74 (d, 2H); 2.02 (t, 2H); 2.30-2.40(m, 1H); 2.60 (t, 2H); 2.89 (d, 2H); 3.65 (s, 2H); 3.98 (s, 3H); 4.26(dd, 2H); 4.29-4.34 (m, 2H); 4.40 (t, 2H); 6.83 (d, 1H); 6.92 (s, 1H);7.98 (s, 1H); 8.10 (s, 1H); 8.12 (d, 1H).

Example 1136-[({1-[2-(6-Chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-1,2,4-benzotriazin-3(4H)-one1-oxide (Intermediate 205, 0.517 g) was reacted with3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (117 mg) and sodium acetoxyborohydride (340 mg) asdescribed for Example 107. Chromatography on silica gel with 0-20%methanol in dichloromethane gave 60 mg of the title compound as aceticacid salt.

MS (ESI) 486 (MH⁺) for C₂₂H₂₄ClN₇O₄

¹H NMR (DMSO-D6) δ 1.13-1.24 (m, 2H); 1.69-1.79 (m, 2H); 2.02 (t, 2H);2.31-2.42 (m, 1H); 2.57 (t, 2H); 2.88 (d, 2H); 3.27-3.39 (m, 2H); 3.67(s, 2H); 4.26 (t, 2H); 4.60 (s, 2H); 7.00 (d, 1H); 7.28 (d, 1H); 7.43(dd, 1H); 7.91 (d, 1H); 8.20 (d, 1H); 11.15 (s, 1H).

Intermediate 205:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-1,2,4-benzotriazin-3(4H)-one1-oxide

tert-Butyl{1-[2-(6-chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 206, 0.65 g) was deprotected with TFA as described forIntermediate 197 to give the crude free base of the product, 0.517 g.

MS (ESI) 324 (MH⁺) for C₁₄H₁₈ClN₅O₂

Intermediate 206: tert-Butyl{1-[2-(6-chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}carbamate

6-Chloro-1,2,4-benzotriazin-3(4H)-one 1-oxide (FR 2621583, 1.50 g) wasdeprotonated with sodium hydride (0.42 g, 60% in oil) and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (1 equivalent) as described for Intermediate 2. Theresidue obtained after aqueous work up was suspended in diethyl etherand filtered to yield 1.30 g of product.

MS (ESI) 424 (MH⁺) for C₁₉H₂₆ClN₅O₄

¹H NMR (CDCl₃) δ 1.30-1.41 (m, 2H); 1.44 (s, 9H); 1.88-1.96 (m, 2H);2.21-2.30 (m, 2H); 2.74 (t, 2H); 2.83-2.92 (m, 2H); 3.41-3.52 (m, 1H);4.27 (t, 2H); 4.34-4.45 (m, 1H); 7.30 (dd, 1H); 7.53 (d, 1H); 8.27 (d,1H).

Example 1146-Chloro-4-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-1,2,4-benzotriazin-3(4H)-one1-oxide

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-1,2,4-benzotriazin-3(4H)-one1-oxide (Intermediate 205, (0.25 g) was reacted with2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(0.14 g) and sodium acetoxyborohydride (0.34 g) as described for Example107. Chromatography on silica gel with 0-20% methanol in dichloromethanegave 60 mg of the title compound as acetic acid salt (0.37 g).

MS (ESI) 473 (MH⁺) for C₂₂H₂₅ClN₆O₄

1H NMR (DMSO-D6) δ 1.14-1.25 (m, 2H); 1.68-1.78 (m, 2H); 2.02 (t, 2H);2.31-2.42 (m, 1H); 2.57 (t, 2H); 2.88 (d, 2H); 3.67 (s, 2H); 4.22-4.30(m, 4H); 4.33 (dd, 2H); 6.93 (s, 1H); 7.44 (dd, 1H); 7.91 (d, 1H); 8.00(s, 1H); 8.21 (d, 1H).

Example 1156-[({1-[2-(6-Chloro-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-1,2,4-benzotriazin-3(4H)-one(Intermediate 207, 67 mg) was reacted with3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (360 mg) and sodium acetoxyborohydride (76 mg) as describedfor Example 107. Chromatography on silica gel with 0-20% methanol indichloromethane and trituration from ether gave 33 mg of the titlecompound.

MS (ESI) 470 (MH⁺) for C₂₂H₂₄ClN₇O₃

¹H NMR (DMSO-D6) δ 1.30-1.42 (m, 2H); 1.88-1.97 (m, 2H); 1.98-2.08 (n,2H); 2.58-2.67 (m, 2H); 2.90-3.02 (m, 2H); 3.28-3.34 (m, 2H); 3.95-4.07(m, 2H); 4.26 (t, 2H); 4.66 (s, 2H); 7.08 (d, 1H); 7.39 (d, 1H); 7.56(dd, 1H); 7.87 (d, 1H); 8.43 (d, 1H); 11.27 (s, 1H).

Intermediate 207:4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-chloro-1,2,4-benzotriazin-3(4M-one

tert-Butyl{1-[2-(6-chloro-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 208, 74 mg) was deprotected with TFA as described forIntermediate 197 to give the crude free base of the product, 67 mg.

MS (ESI) 307 (MH⁺) for C₁₄H₁₈ClN₅O

Intermediate 208: tert-Butyl{1-[2-(6-chloro-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}carbamate

To a solution of tert-butyl{1-[2-(6-chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 206) (0.43 g) in acetic acid (8 mL) and water (2 mL) wasadded zinc dust (0.50 g). After 30 minutes, the solution was filteredand the filtrate concentrated. The residue was then treated withpotassium ferricyanide (1.0 g) in water (20mL). After 2 hours, thereaction was diluted with ethyl acetate. The aqueous layer wascollected, the pH adjusted with solid Na₂CO₃ and extracted with ethylacetate. The combined organic washes were dried (Na₂SO₄), filtered andconcentrated. The residue was purified by chromatography on silica gelwith 0-25% acetone in dichloromethane to yield 66 mg of the product.

MS (ESI) 407 (MH⁺) for C₁₉H₂₆ClN₅O₃

¹H NMR (CDCl₃) δ 1.32-1.40 (m, 2H); 1.44 (s, 9H); 1.91 (d, 2H);2.20-2.30 (m, 2H); 2.75 (t, 2H); 2.87 (d, 2H); 3.40-3.52 (m, 1H); 4.24(t, 2H); 4.40 (s, 1H); 7.42 (dd, 1H); 7.46 (s, 1H); 8.38 (d, 1H).

Example 1164-(2-{(2S,5R)-5-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-2-yl}ethyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile

The product was obtained following the procedure described for Example105, except, the enantiomer of Intermediate 183, tert-butyl(2S,5R)-5-amino-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate(prepared by the exact route as Intermediate 183, but starting from1-tert-butyl 2-ethyl(2S,5S)-5-{[tert-butyl(dimethyl)silyl]oxy}piperidine-1,2-dicarboxylate,the enantiomer of Intermediate 191) was reacted with2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde to yield the namedcompound.

MS (ESI) 449 (MH⁺) for C₂₄H₂₇N₅O₄

¹H NMR (DMSO-D6) δ ppm 1.42-1.81 (m, 3H); 1.85-2.03 (m, 1H); 2.16 (d,1H); 2.28 (d, 1H); 2.98-3.11 (m, 1H); 3.38-3.58 (m, 1H); 3.68 (d, 2H);4.28 (s, 2H); 4.38 (dd, 4H); 4.80 (s, 2H); 7.18 (d, 1H); 7.31 (s, 1H);7.52 (d, 1H); 7.75 (s, 1H); 8.26 (s, 1H); 9.46-9.79 (m, 2H); 9.98 (s,1H).

Example 1176-[({1-[2-(7-Bromo-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one(Intermediate 209) (2.0 mmol),(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (356 mg, 2.0 mmol) and sodium cyanoborohydride (496 mg, 4equiv) were reacted as described under Example 21 to give the product asan off-white solid 420 mg (41% yield).

MS (ESP): 517, 52 (MH⁺) for C₂₂H₂₅BrN₆O₄

¹H-NMR (DMSO-d₆) δ: 1.13 (t, 2H); 1.34 (q, 5H); 1.85 (d, 2H); 1.98 (t,2H); 2.45 (m, 2H); 2.71 (m, 1H); 2.91 (d, 2H); 3.00 (m, 2H); 3.89 (m,2H); 3.99 (m, 2H); 4.63 (s, 2H); 4.85 (s, 2H); 7.05 (d, 1H); 7.35 (d,1H); 7.94 (dd, 1H); 11.25 (bs, 1H).

Intermediate 209:1-[2-(4-Aminopiperidin-1-yl)ethyl]-7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

tert-Butyl{1-[2-(7-bromo-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl]piperidin-4-yl}carbamate(Intermediate 210) (0.85 g) was reacted as described for Intermediate14. The crude trifluoro acetate of the title compound was used withoutfurther purification for the next step (quantitative yield).

MS (ESP): 355/357 (MH⁺) for C₁₄H₁₉BrN₄O₂

Intermediate 210: tert-Butyl{1-[2-(7-bromo-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl]piperidin-4-yl}carbamate

6-Bromo-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Intermediate 211) (460mg, 2.0 mmol) was deprotonated with sodium hydride and alkylated with2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate(Intermediate 6) (2.1 mmol) as described for Intermediate 2.Chromatography on silica gel with methanol/dichloromethane gave theproduct as an oil (0.85 g, 93% yield).

MS (ESP): 455, 457 (MH⁺) for C₁₉H₂₇BrN₄O₄

Intermediate 211: 7-Bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

Ethyl [(5-bromo-3-nitropyridin-2-yl)oxy]acetate (intermediate 212) (4.3g, 14.1 mmol) was dissolved in anhydrous THF (10 mL) and concentratedHCl (10 mL) was added at 0° C. Tin chloride (5.0 g, 26.4 mmol) was addedin small portions. The reaction was stirred for 1 hr and heated at 65°C. overnight. The reaction mixture was concentrated under reducedpressure, extracted with chloroform, dried over magnesium sulfate andconcentrated. Chromatography on silica gel with methanol/chloroform gavethe product as a light pink solid (1.2 g, 37% yield).

MS (ESP): 229/231(MH⁺) for C₇H₅BrN₂O₂

¹H-NMR (DMSO-d₆) δ: 4.80 (s, 2H); 7.32 (s, 1H); 7.87 (s, 1H); 10.94 (bs,1H).

Intermediate 212: Ethyl [(5-bromo-3-nitropyridin-2-yl)oxy]acetate

A mixture of 5-bromo-2-chloropyridin-3-ol (4.73 g, 19.9 mmol) and ethylglycolate (2.9 g, 27.8 mmol) in anhydrous dioxane (20 mL) was treatedwith sodium hydride (1.12 g, 60% in mineral oil, 28 mmol) in portions(exothermic reaction!). The reaction was then quenched with water andextracted with chloroform and dried over magnesium sulfate.Chromatography on silica gel with ethyl acetate/hexanes gave the productas a light yellow solid (4.8 g, 79% yield).

MS (ESP): 305, 307(MH⁺) for C₉H₉BrN₂O₅

¹H-NMR (DMSO-d₆) δ ppm: 1.17 (t, 3H); 4.12 (q, 2H); 5.10 (s, 2H); 8.64(s, 1H); 8.76 (s, 1H).

Example 1182-Oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonitrile

and

Example 1192-Oxo-1-[2-(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl)methyl]amino}piperidin-1-yl)ethyl]-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide

A mixture of6-[({1-[2-(7-bromo-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one(Example 117) (110 mg, 0.21 mmol), zinc cyanide (80 mg, 0.683 mmol) andtetrakis(triphenylphosphine) palladium(0) (25 mg, 0.0215 mmol) inanhydrous DMF (2.5 mL) over molecular sieves 3 Å was vortexed and thenheated in the microwave at 200° C. for one hour. Reverse phasechromatography and generation of the free base as described for Example21 gave 20 mg (20%) of Example 118 and 20 mg (20%) of Example 119, bothas off-white solids.

Example 118

MS (ESP): 464(MH⁺) for C₂₃H₂₅N₇O₄

¹H-NMR (DMSO-d₆) δ: 1.74 (m, 2H); 2.18 (m, 2H); 3.02 (m, 2H); 3.80 (m,2H); 3.90 (m, 2H); 4.23 (m, 4H); 4.70 (s, 2H); 5.01 (s, 2H); 7.11 (d,1H); 7.44 (d, 1H); 8.08 (s, 1H); 8.40 (s, 1H); 9.28 (s, 1H); 9.75 (bs,1H); 11.35 (bs, 1H).

Example 119

MS (ESP): 482(MH⁺) for C₂₃H₂₇N₇O₅

¹H-NMR (DMSO-d₆) δ: 1.74 (m, 2H); 2.36 (m, 2H); 3.10 (m, 2H); 3.80 (m,2H); 4.23 (m, 2H); 4.32 (m, 4H); 4.56 (s, 2H); 4.70 (s, 2H); 4.94 (s,4H); 7.11 (d, 1H); 7.44 (d, 1H); 7.62 (s, 1H); 7.91 (s, 1H); 8.08 (s,1H); 8.38 (s, 1H); 9.30 (bs, 2H); 9.60 (bs, 1H); 11.35 (bs, 1H).

Example 1201-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]-2-methylpiperidin-1-yl}ethyl)-5,7-difluoroquinolin-2(1H)-one

A solution of1-[2-(4-amino-2-methylpiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one(Intermediate 213, crude, 220 mg, 0.69 mmol) and2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144)(114 mg, 0.69 mmol) in dry dichloroethane/methanol (4 mL, 4:1) washeated over 3 Å molecular sieves at 80° C. for 3 hours. The reactionmixture was cooled to 0° C., and sodium triacetoxy borohydride (299 mg,1.38 mmol) was added. The resulting reaction mixture was stirred at roomtemperature for 16 hours and then was filtered through a 0.45 μmmembrane and concentrated to dryness under reduced pressure. The residuewas taken up in dichloromethane (20 mL) and saturated aqueous sodiumhydrogen carbonate solution (5 mL). The pH of the aqueous phase wasadjusted to pH˜10 with 1M aqueous sodium hydroxide solution. The aqueousphase was back extracted twice with dichloromethane (4×20 mL) and thecombined organic phases were dried over sodium sulfate and concentratedunder reduced pressure. Chromatography on silica gel withdichloromethane/methanol (17:3) gave 195 mg (69%) of the title compoundas a white foam.

MS (ESP): 471.22 (MH⁺) for C₂₅H₂₈F₂N₄O₃

¹H NMR (300 MHz, DMSO-d₆) δ: 0.82-0.91 (m, 4H); 1.16-1.26 (m, 1H);1.74-1.90 (m, 2H); 2.16-2.25 (m, 2H); 2.34-2.42 (m, 2H); 2.85-2.95 (m,1H); 3.08 (d, 1H, J=11.5 Hz); 3.76 (s, 2H); 4.27-4.34 (m, 6H); 6.63 (d,1H, J=9.8 Hz); 6.96 (s, 1H); 7.18-7.32 (m, 2H); 7.94 (d, 1H, J=9.8 Hz);8.03 (s, 1H).

The intermediates for Example 120 were prepared as follows:

Intermediate 213:1-[2-(4-Amino-2-methylpiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one

A solution of1-{2-[4-(dibenzylamino)-2-methylpiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one(Intermediate 214 358 mg, 0.71 mmol) in methanol (6 mL) was treated withpalladium hydroxide on carbon (100 mg). The reaction was stirred at roomtemperature under hydrogen gas for 18 hours, filtered through celite,rinsed with methanol (100 mL), and concentrated under reduced pressureto afford 225 mg (96%) of a yellow oil.

MS (ESP): (MH⁺) for C₁₇H₂₁F₂N₃O.

¹H-NMR (DMSO-d₆) δ: 0.74-0.87 (m, 4H); 1.04-1.17 (dq, 1H, J=12.1, 11.9,3.7 Hz); 1.54-1.67 (m, 2H); 2.16-2.26 (m, 2H); 2.30-2.39 (m, 1H);2.84-2.95 (m, 1H); 3.02-3.08 (m, 1H); 4.26 (t, 2H, J=6.7 Hz); 6.63 (d,1H, J=9.8 Hz); 7.17-7.31 (m, 2H); 7.94 (d, 1H, J=9.8 Hz).

Intermediate 214:1-{2-[4-(Dibenzylamino)-2-methylpiperidin-1-yl]ethyl}-5,7-difluoroquinolin-2(1H)-one

A solution of 5,7-difluoroquinolin-2(1H)-one (40 mg, 1.9 mmol) in drydimethylformamide (DMF) (5 mL) was treated at 0° C. with a cooling bathunder stirring with sodium hydride (80 mg, 60% in oil, 2.0 mmol). Thecooling bath was removed and the mixture was stirred for 30 minutes atroom temperature. A solution of2-[4-(benzylamino)-2-methylpiperidin-1-yl]ethyl methanesulfonate in DMF(Intermediate 215, 0.58 mmol/mL, 3.5 mL, ˜2.03 mmol) was then added andthe resulting mixture was stirred over night at room temperature. TheDMF was removed under reduced pressure, and the residue was taken up inethyl acetate (100 mL) and saturated aqueous sodium hydrogencarbonatesolution (30 mL). The aqueous phase was back extracted once with ethylacetate (50 mL). The combined organic phases were dried over sodiumsulfate and concentrated under reduced pressure. Chromatography onsilica gel with hexanes/acetone (2:1) gave 365 mg (39% yield) of theproduct as a yellow solid.

MS (ESP): 502 (MH⁺) for C₃₁H₃₃F₂N₃O

¹H-NMR (DMSO-d_(d)) δ: 0.89 (d, 3H, J=5.5 Hz); 1.10-1.23 (m, 1H);1.46-1.54 (m, 1H); 1.70 (t, 2H, J=14.3 Hz); 2.10-2.16 (m, 2H); 2.35-2.44(m, 2H); 2.82-2.89 (m, 1H); 3.12 (d, 1H, J=10.4 Hz); 3.54 (s, 4H);4.21-4.26 (m, 2H); 6.61 (d, 1H, 9.8 Hz); 7.16-7.34 (m, 12H); 7.95 (d,1H).

Intermediate 215: 2-[4-(Dibenzylamino)2-methylpiperidin-1-yl]ethylmethanesulfonate

A mixture 2-[4-(dibenzylamino)-2-methylpiperidin-1-yl]ethanol(Intermediate 216, 660 mg, 1.9 mmol) in dry dichloromethane (6 mL) andtriethyl amine (0.375 mL, 2.7 mmol) was treated at 0° C. withmethanesulfonyl chloride (0.175 mL, 8.4 mmol). After 45 minutes thereaction was complete by TLC (chloroform/methanol 6:1, rf 0.54).Potassium phosphate buffer (pH 7, 1M, 25 mL) was added, dichloromethanewas removed under reduced pressure and it was extracted with ice coldethyl acetate (2×100 mL) and dried over sodium sulfate. The solvent wasremoved under reduced pressure and the crude preparation of the mesylatewas used without delay for the next step.

MS (ESP): 417.18 (MH⁺) for C₂₃H₃₂N₂O₃S.

Intermediate 216: 2-[4-(Dibenzylamino)-2-methylpiperidin-1-yl]ethanol

To a solution of N,N-dibenzyl-2-methylpiperidin-4-amine (Intermediate217, 880 mg, 3.0 mmol) in acetonitrile (6 mL) was added triethylamine(0.85 ml, 6.0 mmol) and 2-bromoethanol (0.32 mL, 4.5 mmol). The reactionis stirred at 70° C. at 300 watts in the microwave for 20 minutes.Acetonitrile was removed under reduced pressure, the residue was takenup in dichloromethane (100 mL) and saturated aqueous sodium hydrogencarbonate solution (30 mL) and the aqueous phase was back extractedthree times with dichloromethane (3×70 mL). The combined organic phaseswere dried over sodium sulfate and concentrated to dryness under reducedpressure. Chromatography of the residue on silica gel withdichloromethane/methanol (10:1) gave 660 mg (65% yield) of the productas an orange solid.

MS (ESP): 339.22 (MH⁺) for C₂₂H₃₀N₂O.

¹H-NMR (DMSO-d₆) δ: 1.01 (d, 3H, J=5.8 Hz), 1.22-1.34 (m, 1H); 1.48-1.56(m, 1H); 1.69 (d, 2H, J=11.1 Hz); 1.95-2.11 (m, 2H); 2.14-2.30 (m, 1H);2.38-2.43 (m, 1H); 2.64-2.80 (m, 1H); 2.84-3.00 (m, 1H); 3.37-3.41 (m,1H); 3.55 (s, 4H); 4.24-4.35 (m, 1H); 7.15-7.22 (m, 2H); 7.24-7.34 (m,8H).

Intermediate 217: N,N-Dibenzyl-2-methylpiperidin-4-amine

A mixture of ethyl 4-(dibenzylamino)-2-methylpiperidine-1-carboxylate(Intermediate 218, 1.28 g, 3.78 mmol) in dry isopropyl alcohol (30 mL)was added potassium hydroxide (0.65 mL, 8.4 mmol). The reaction wasstirred at 105° C. for 6 hours. 2-Propanol was removed under reducedpressure, the residue was taken up in dichloromethane (100 mL), filteredthrough a 0.5 μm membrane, and concentrated under reduced pressure.Chromatography of the residue on silica gel withdichloromethane/methanol/ammonium hydroxide (85:15:0.1) gave 882 mg (79%yield) of the product as a red oil.

MS (ESP): 295.18 (MH⁺) for C₂₀H₂₆N₂.

¹H-NMR (DMSO-d₆) δ: 0.98 (d, 3H, J=5.8 Hz); 1.07-1.14 (m, 1H); 1.37 (dq,1H, J=12.0, 4.2 Hz); 1.68 (t, 2H, J=13 Hz); 2.26-2.36 (m, 2H); 2.40-2.46(m, 1H); 2.91-2.97 (m, 1H); 3.56 (s, 4H); 7.16-7.20 (m, 2H); 7.25-7.34(m, 8H).

Intermediate 218: Ethyl4-(dibenzylamino)-2-methylpiperidine-1-carboxylate

A mixture of ethyl 4-(benzylamino)-2-methylpiperidine-1-carboxylate(Intermediate 219, 1.57 g, 5.7 mmol), cesium carbonate (3.72 g, 11.4mmol) and benzyl bromide (1.36 mL, 11.4 mmol) in dry DMF (20 mL) washeated at 80° C. for 16 hours. The DMF was removed under reducedpressure, the residue was taken up in ethyl acetate (150 mL) and water(75 mL) and the aqueous phase was back extracted once with ethyl acetate(3×150 mL). The combined organic phases were washed with brine (100 mL)and were dried over sodium sulfate. Chromatography on silica gel withhexanes/ethyl acetate (3:2) gave 1.43 g (68% yield) of the product as ayellow oil.

MS (ESP) 367 (MH⁺) for C₂₃H₃₀N₂O₂.

¹H-NMR (DMSO-d_(d)) δ: 1.07-1.16 (m, 6H); 1.47-1.61 (m, 2H); 1.72-1.93(m, 2H); 2.56-2.70 (m, 1H); 3.11-3.19 (m, 1H); 3.48-3.63 (m, 6H);3.89-4.00 (m, 2H); 7.17-7.21 (m, 2H); 7.29-7.38 (m, 8H).

Intermediate 219: Ethyl 4-(benzylamino)-2-methylpiperidine-1-carboxylate

A solution of ethyl 2-methyl-4-oxopiperidine-1-carboxylate (2.20 grams,11.9 mmol) and benzyl benzylamine in dichloroethane/methanol (4:1, 50mL) was heated over 3 Å molecular sieves at 90° C. for 16 hours. Thereaction mixture was cooled to 0° C., and sodium triacetoxy borohydride(5.03 g, 23.8 mmol) was added. The resulting reaction mixture wasstirred at room temperature for 30 minutes and then was filtered througha 0.45 μm membrane and concentrated to dryness under reduced pressure.The residue was taken up in aqueous 1N HCl solution and washed withether (2×50 mL). The pH of the aqueous phase was adjusted to a pH ofapproximately 7 with 1M aqueous sodium bicarbonate solution. The aqueousphase was back extracted twice with ether (4×50 mL) and the combinedorganic phases were dried over sodium sulfate and concentrated underreduced pressure. Chromatography on silica gel withdichloromethane/methanol (94:6) gave 1.57 g (47% yield) of a yellow oil.

MS (ESP): 277 (MH⁺) for C₁₆H₂₄N₂O₂.

¹H-NMR (DMSO-d₆) δ: 1.15 (t, 3H, J=7.1 Hz); 1.30 (d, 3H, J=6.8 Hz);1.52-1.59 (m, 3H); 1.61-1.71 (m, 1H); 2.80-2.82 (m, 1H); 3.22-3.27 (m,1H); 3.57-3.73 (m, 3H); 3.95-4.06 (m, 3H); 7.18-7.34 (m, 5H).

Example 1211-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-2-oxo-1,2-dihydroquinoline-7-carbonitrile

A mixture of7-chloro-1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-2(1H)-one(2.11 g, crude, ˜3.47 mmol) and zinc cyanide (244 mg, 2.1 mmol) in dryDMF (8 mL) was degassed and flushed with nitrogen three times. Zinc (174mg, 0.059 mmol, 51.6 mM solution in heptane) was added, followed by4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63 mg, 0.11 mmol) andtris(dibenzylideneacetone)dipalladium(0) (100 mg, 0.11 mmol) and it wasdegassed and flushed with nitrogen like above. The mixture was stirredfor 30 minutes at room temperature and then degassed and flushed withnitrogen again. It was heated at 120° C. for 3 hours. The solvent wasremoved under reduced pressure and the residue taken up inchloroform/isopropyl alcohol (3:1, 50 mL) and filtered through celiteand concentrated under reduced pressure. Chromatography by reverse phase(Column: Atlantis Hilic; Gradient: 90% ACE/0.1% TFA; 5% Water/0.1% TFA;and 5% Isopropanol/0.1% TFA; Flow Rate: 1 mL/min.) afforded 418 mg (20%)of a brown oil as a TFA salt.

MS (ESP): 447.14 (MH⁺) for C₂₄H₂₆N₆O₃

¹H NMR (300 MHz, DMSO-d₆) δ: 1.75-1.87 (m, 2H); 2.29-2.38 (d, 2H, J=12.6Hz); 3.00-3.20 (m, 2H); 3.37-3.49 (m, 2H); 3.90 (d, 2H, J=12.6 Hz); 4.24(br s, 2H); 4.35 (d, 2H, J=4.6 Hz); 4.39 (d, 2H, J=4.6 Hz); 4.62-4.72(m, 2H); 6.95 (d, 1H, J=9.6); 7.12 (s, 1H); 8.02 (d, 1H, J=7.7 Hz); 8.11(d, 1H, J=9.6 Hz); 8.21 (s, 1H); 8.47 (d, 1H, J=7.7); 9.18-9.45 (m, 2H).

Example 122Cis±1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylicacid

A solution of methylCis(±)-1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate(Example 123) (105 mg, 0.204 mmol) in methanol (1 mL) was treated with asolution of sodium hydroxide (1N, 1 mL) the reaction was warmed to 30°C. for 18 hours. The temperature was increased to 60° C. for 6 hours.The solvents were evaporated, the reaction was diluted with ethylacetate and water. The pH was adjusted to 7 with 1N HCl. The layers wereseparated. The aqueous phase was extracted with ethyl acetate (2×20mL).The organic layers were combined dried over magnesium sulfate andconcentrated at reduced pressure. The residue was taken up anddichloromethane and precipitated with ether in a dry ice/acetone bath.The solvent was decanted. The solid was dried under high vacuum toobtain 21 mg (20%) of an off-white solid.

MS(ESP): 501 (MH⁺) for C₂₇H₃₀F₂N₂O₅

¹H-NMR (400 MHz, DMSO-d₆) δ1.14-1.26 (m, 1H) 1.41-1.53 (m, 1H) 1.57-1.68(m, 2H) 1.74-1.84 (m, 1H) 1.98-2.10 (m, 1H) 2.89-2.97 (m, 1H) 2.98-3.04(m, 1H) 3.04-3.12 (m, 1H) 3.12-3.20 (m, 1H) 3.22-3.34 (m, 1H) 3.34-3.45(m, 2H) 3.71 (s, 3H) 3.81-3.86 (m, 1H) 3.88-3.96 (m, 3H) 4.46 (s, 2H)6.47-6.58 (m, 2H) 6.63 (s, 1H) 6.85 (d, 2H) 7.06-7.18 (m, 2H) 7.39-7.48(m, 1H) 8.11 (s, 1H)

Example 123 Methylcis(±)1-[(2E)-3-(2,5-difluorophenyl)prop-2-en-1-yl]-4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate

A solution of methyl4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate(Intermediate 220) (150 mg, 0.414 mmol) in ethanol (2 mL) was treatedwith K₂CO₃ (63 mg, 0.455 mmol) followed by a solution of2-[(1E)-3-chloroprop-1-en-1-yl]-1,4-difluorobenzene (Intermediate 124)(86 mg, 0.455 mmol) in ethanol (1 mL). The reaction was warmed to 40° C.for 18 hours. The reaction was partitioned between ethyl acetate andwater. The aqueous layer was extracted with dichloromethane (2×20 mL).The organic extracts were combined, dried over MgSO₄ and concentrated atreduced pressure to obtain a yellow oil. Chromatography on silica geleluting with (0-2.5%) methanol in dichloromethane gave the titlecompound as a yellow oil (120 mg, 56%).

MS(ESP): 515 (MH⁺) for C₂₈H₃₂F₂N₂O₅

¹H-NMR (400 Mz, DMSO-d₆) δ 1.19-1.30 (m, 2H) 1.39-1.49 (m, 2H) 1.49-1.61(m, 2H) 1.66-1.78 (m, 2H) 2.16-2.28 (n, 1H) 2.36 (s, 1H) 2.64-2.75 (m,1H) 3.03-3.15 (m, 2H) 3.54 (s, 3H) 3.73 (s, 3H) 3.81-3.92 (n, 2H) 4.52(s, 2H) 6.39-6.51 (m, 1H) 6.56 (dd, J=8.6, 2 Hz, 2H) 6.71 (d, J=2 Hz,1H) 6.92 (d, J=8.6 Hz, 1H) 7.07-7.18 (m, 1H) 7.18-7.30 (m, 1H) 7.46-7.57(n, 1H).

The intermediates for Example 2 were prepared as follows:

Intermediate 220: Methyl4-[3-(6-methoxy-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)propyl]piperidine-3-carboxylate

To an ice-cooled solution of 6-methoxy-2H-1,4-benzoxazin-3(4H)-one(Intermediate 48) (407 mg, 2.29 mmol) in DMF was added sodium hydride(110 mg, 2.75 mmol). After stirring for 2 hours a solution of1-tert-butyl 3-methyl4-{3-[(methylsulfonyl)oxy]propyl}piperidine-1,3-dicarboxylate (868 mg,˜2.29 mmol) (Intermediate 132) in DMF (5 mL) was added. The reaction wasallowed to stir at room temperature for five days. The reaction wasdiluted with ethyl acetate and water. The pH was adjusted toapproximately 3 with 1N HCl. The layers were separated. The aqueouslayer was extracted with ethyl acetate (3×30 mL). The combined organiclayers were washed with water (4×50 mL), dried over magnesium sulfateand concentrated at reduced pressure to obtain a semi-solid.Chromatography on silica gel eluting with (0-2.5%) methanol indichloromethane gave the product as a mixture of diastereomers. Reversephase separation using a 50-60% gradient of acetonitrile in water with0.1% trifluoroacetic acid gave the cis diastereomer as the fastereluting peak. Upon evaporation of the organic components and extractionof the aqueous with 20% methanol in dichloromethane 150 mg of the cisdiastereomer was obtained.

¹H NMR (CDCl₃): δ 1.19-1.30 (m, 1H); 1.32-1.40 (m, 2H); 1.64-1.75 (m,2H); 1.77-1.89 (m, 2H); 1.94-2.04 (m, 1H); 2.93-3.01 (m, 1H); 3.06-3.11(m, 1H); 3.13-3.20 (m, 1H); 3.47-3.53 (m, 1H); 3.54-3.60 (m, 1H); 3.74(s, 3H); 3.79 (s, 3H); 3.82-3.90 (m, 1H); 3.90-4.00 (m, 1H); 4.49-4.57(m, 2H); 6.49-6.56 (m, 2H); 6.89-6.97 (m, 1H).

The trans compound was obtained as a mixture of amine and Boc protectedmaterial (138 mg) through neutralization of the aqueous layer withsodium bicarbonate before extraction with 20% methanol indichloromethane. The mixture was dissolved in ethanol (3 mL) and heatedin the microwave at 150° C. for four hours.

MS(ESP): 363 (MH⁺) for C₁₉H₂₆N₂O₅

Example 1241-(2-{4-[(2,3-Dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxy-3,4-dihydroquinoxalin-2(1H)-one

To a solution of1-(2-{4-[(2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-1-yl}ethyl)-7-methoxyquinoxalin-2(1H)-one(Example 72, 0.125 g) in ethanol (4 mL) was added sodium borohydride (40mg). After 3 hour at room temperature, additional sodium borohydride (47mg) was added. After 30 minutes the reaction was quenched with acetoneand concentrated. Chromatography on silica gel with a gradient ofdichloromethane to 20% methanol in dichloromethane gave 108 mg of theproduct as a colorless solid.

MS (ESI) 454 (MH⁺) for C₂₄H₃₁N₅O₄

¹H-NMR (DMSO-d₆) δ (ppm): 1.36 (m, 2H); 1.78-1.88 (m, 2H); 1.98 (t, 2H);2.41 (t, 2H); 2.52-2.60 (m, 1H); 2.89 (d, 2H); 3.63 (d, 2H); 3.67 (s,3H); 3.77-3.87 (m, 2H); 3.88-3.95 (m, 2H); 4.25-4.30 (m, 2H); 4.31-4.36(m, 2H); 5.65 (s, 1H); 6.46 (dd, 1H); 6.62 (d, 1H); 6.66 (d, 1H);6.95-7.01 (m, 1H); 8.05 (s, 1H).

Example 1255,7-Difluoro-1-[2-(4-{[(1-oxo-1,3-dihydro-2-benzofuran-5-yl)methyl]amino}piperidin-1-yl)ethyl]quinolin-2(1H)-one

The compound was prepared following the procedure described for Examples87-96.

MS (ES): 454 (MH⁺) for C₂₅H₂₅N₃O₃

¹H-NMR (DMSO-d₄) δ (ppm): 1.83 (s, 2H); 2.32 (s, 2H); 3.07 (s, 1H); 3.31(s, 2H); 3.45 (s, 2H); 3.80 (s, 2H); 4.39 (s, 2H); 4.53 (s, 2H); 5.45(s, 2H); 6.66 (d, 1H); 7.29 (t, 1H); 7.42 (d, 1H); 7.73 (d, 1H); 7.80(s, 1H; 7.94 (d, 1H); 8.01 (d, 1H); 9.49 (s, 1H).

Example 1266-[({1-[2-(7-Methoxy-2-oxoquinoxalin-1(2H)-yl)propyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

1-[2-(4-aminopiperidin-1-yl)-1-methylethyl]-7-methoxyquinoxalin-2(1H)-one(Intermediate 221) (160 mg crude, 0.51 mmol),3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO2004/058144) (91 mg, 0.51 mmol), and sodium triacetoxy borohydride (320mg, 1.5 mmol) were reacted as described according to Example 69.Chromatography on silica gel eluting with 5% methanol/dichloromethanecontaining 0.25% ammonium hydroxide gave 105 mg (63%) of the titlecompound as an off-white solid.

MS (ESP): 479 (MH⁺) for C₂₅H₃₀N₆O₄

¹H NMR (DMSO-D6) δ (ppm): 0.96 (d, 3H); 0.99-1.14 (m, 2H); 1.71 (t, 2H);1.95 (s, 1H); 2.10 (t, 1H); 2.22-2.41 (m, 2H); 2.89-3.01 (m, 1H);3.03-3.14 (m, 1H); 3.64 (s, 2H); 3.90 (s, 3H); 4.11 (q, 1H); 4.27-4.40(m, 1H); 4.55-4.66 (m, 2H); 6.93-7.04 (m, 3H); 7.23-7.33 (m, 1H);7.69-7.80 (m, 1H); 8.04 (s, 1H); 11.16 (s, 1H).

Intermediate 221:1-[2-(4-Aminopiperidin-1-yl)-1-methylethyl]-7-methoxyquinoxalin-2(1H)-one

A solution of tert-butyl{1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propyl]piperidin-4-yl}carbamate(Intermediate 222, 200 mg, 0.48 mmol) in dichloromethane (30 mL) wastreated with trifluoroacetic acid (3 mL). After 2 hours, the reactionwas concentrated to dryness. The residue was partitioned between 15%methanol/chloroform. The aqueous phase was re-extracted 3× with 15%methanol/chloroform. The combined organic phases were dried overmagnesium sulfate, filtered, and concentrated to dryness giving 160 mg(100%) of the crude product as an oil.

MS (ESP): 317 (MH⁺) for C₁₇H₂₄NO₄O₂

Intermediate 222: tert-Butyl{1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)propyl]piperidin-4-yl}carbamate

A solution of 7-methoxyquinoxalin-2(1H)-one (Intermediate 148, 590 mg,3.35 mmol) in dry DMF (10 mL) was cooled in an ice bath under nitrogenand treated with sodium hydride (60%, 160 mg, 4.02 mmol). The reactionwas stirred at room temperature for ˜90 minutes. The reaction was againcooled in an ice bath and treated with a solution of2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-1-methylethylmethanesulfonate in dry DMF (Intermediate 223, ˜0.43 mmol/ml, 4.3 mmol).The reaction was stirred at room temperature overnight. The reactionmixture was concentrated to dryness. Residual DMF was co-evaporated 1×with toluene. The resulting residue was partitioned between ethylacetate and water. The aqueous phase was re-extracted 3× with ethylacetate. The organic phases were combined, dried over magnesium sulfate,filtered, and concentrated to dryness. Chromatography on silica gel with25% acetone/hexanes gave 410 mg (29%) of product which contained ˜10%starting material (7-methoxyquinoxalin-2(1H)-one). This material wasused directly in the next step.

MS (ESP): 417 (MH⁺) for C₂₂H₃₂N₄O₄

¹H NMR (DMSO-D6) δ (ppm): 0.96 (d, 3H); 1.10-1.26 (m, 2H); 1.31-1.42 (m,9H); 1.53-1.72 (m, 2H); 2.14 (t, 1H); 2.37 (t, 1H); 2.94 (d, 1H);3.04-3.15 (m, 2H); 3.87-3.96 (m, 3H); 4.06-4.20 (m, 2H); 4.32 (dd, 1H);6.71 (d, 1H); 6.95-7.05 (m, 2H); 7.71-7.78 (m, 1H); 8.04 (s, 1H).

Intermediate 223:2-{4-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-1-methylethylmethanesulfonate

tert-Butyl [1-(2-hydroxypropyl)piperidin-4-yl]carbamate (Intermediate224, 1.1 g, 4.3 mmol), triethylamine (0.90 mL, 6.5 mmol) andmethanesulfonyl chloride (0.37 mL, 4.7 mmol). Were reacted as describedfor Intermediate 6. The crude mesylate was directly used for the nextstep.

Intermediate 224: tert-Butyl[1-(2-hydroxypropyl)piperidin-4-yl]carbamate

tert-Butyl piperidin-4-ylcarbamate (2.0 g, 10.0 mmol),1-bromopropan-2-ol (2.8 g, 20.0 mmol, commercial product which alsocontained 30% of the regioisomer 2-bromopropan-1-ol), triethylamine (4.2mL, 30.0 mmol), and acetonitrile (15 mL) were combined in a microwavevial and heated to 70° C. for 4 hours. The reaction mixture wasconcentrated to dryness. The crude product was partitioned between ethylacetate/water. The aqueous phase was re-extracted 2× with ethyl acetate.The combined organic phases were dried over magnesium sulfate, filtered,and concentrated to dryness. The product was purified by flashchromatography on silica gel eluting with a gradient of 20-30% methanolin dichloromethane to give 1.7 g of the desired product as an oil.

¹H NMR (DMSO-D6) δ ppm 1.01 (d, 3H); 1.26-1.48 (m, 11H); 1.64 (d, 2H);1.85-2.04 (m, 2H); 2.03-2.27 (m, 2H); 2.78 (d, 2H); 3.09-3.29 (m, 1H);3.62-3.81 (m, 1H); 4.23 (d, 1H); 6.75 (d, 1H).

Example 1275,7-Difluoro-1-(2-{4-[(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethyl)amino]piperidin-1-yl}ethyl)quinolin-2(1H)-one

1-[2-(4-Aminopiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one(Intermediate 23) (126 mg, 0.410 mmol),5,6,7,8-tetrahydro-1,8-naphthyridine-2-carbaldehyde (JOC 2004, 69,1959-1966) (66 mg, 0.410 mmol) and sodium triacetoxy borohydride (52 mg,0.82 mmol) were reacted as described for Example 6, to give 84.82 mg ofthe mono acetate salt of the product as a pale yellow foam.

MS (ES): 454.54 (MH⁺) for C₂₅H₂₉F₂N₅O

¹H NMR (DMSO-D6) δ (ppm): 1.12-1.27 (m, 2H); 1.67-1.79 (m, 4H); 2.01 (t,2H); 2.29-2.42 (m, 1H); 2.60 (t, 2H); 2.88 (d, 2H); 3.22 (t, 2H); 3.51(s, 2H); 4.29 (t, 2H); 6.28 (s, 1H); 6.40 (d, 1H); 6.61 (d, 1H); 7.05(d, 1H); 7.16-7.26 (m, 1H); 7.31 (d, 1H); 7.96 (d, 1H).

All cited publications, patents, and patent documents are incorporatedby reference herein, as though individually incorporated by reference.The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

1. A compound that is6-[({1-[2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl]piperidin-4-yl}amino)methyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one,or a pharmaceutically acceptable salt thereof.